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Nanoparticles for Cancer Therapy: Current Progress and Challenges

Shreelaxmi gavas.

1 Department of Life Sciences, GenLab Biosolutions Private Limited, Bangalore, Karnataka 560043 India

Sameer Quazi

2 GenLab Biosolutions Private Limited, Bangalore, Karnataka 560043 India

Tomasz M. Karpiński

3 Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712 Poznań, Poland

Associated Data

Not applicable.

Cancer is one of the leading causes of death and morbidity with a complex pathophysiology. Traditional cancer therapies include chemotherapy, radiation therapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multi-drug resistance pose a substantial challenge for favorable cancer treatment. The advent of nanotechnology has revolutionized the arena of cancer diagnosis and treatment. Nanoparticles (1–100 nm) can be used to treat cancer due to their specific advantages such as biocompatibility, reduced toxicity, more excellent stability, enhanced permeability and retention effect, and precise targeting. Nanoparticles are classified into several main categories. The nanoparticle drug delivery system is particular and utilizes tumor and tumor environment characteristics. Nanoparticles not only solve the limitations of conventional cancer treatment but also overcome multidrug resistance. Additionally, as new multidrug resistance mechanisms are unraveled and studied, nanoparticles are being investigated more vigorously. Various therapeutic implications of nanoformulations have created brand new perspectives for cancer treatment. However, most of the research is limited to in vivo and in vitro studies, and the number of approved nanodrugs has not much amplified over the years. This review discusses numerous types of nanoparticles, targeting mechanisms, and approved nanotherapeutics for oncological implications in cancer treatment. Further, we also summarize the current perspective, advantages, and challenges in clinical translation.

Introduction

Cancer is a generic term for a set of diseases characterized by uncontrolled, random cell division and invasiveness. Extensive efforts over several years have been focused on detecting various risk factors for cancer. For some cancers, etiology has been influentially associated with specific environmental (acquired factors) such as radiation and pollution. However, an unhealthy lifestyle like a poorly balanced diet, tobacco consumption, smoking, stress, and lack of physical activity strongly impacts cancer risk determination [ 1 , 2 ]. While these external factors have been recognized as major causes of cancer, the involvement of mutations of proto-oncogenes, tumor suppressor genes expression patterns, and the genes involved in DNA repair has been tough to estimate. Only 5–10% of cancer cases are linked with inherited genetics [ 3 ]. Advancing age is another crucial risk factor for cancer and many individual cancer types.

Cancer is one of the significant public health problems globally and is the second leading cause of death. According to the American Cancer Society, the number of new cases is anticipated to be 1.9 million by the end of the year 2021 [ 4 ]. The conventional therapeutic approaches used in cancer treatment include surgery, chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy [ 5 , 6 ]. Although chemotherapy and radiation therapy possess cytostasis and cytotoxicity abilities [ 7 ], these approaches are often linked with acute side effects and a high risk of recurrences. The most common side effects that are induced by include neuropathies, suppression of bone marrow, gastrointestinal and skin disorders, hair loss, and fatigue. Besides, there are a few drug-specific side effects such as anthracyclines and bleomycin-induced cardiotoxicity and pulmonary toxicity [ 8 ] (Fig.  1 ).

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Nanoparticles for cancer therapy

The advent of targeted therapy has made growth in precision therapy [ 9 ]. However, there are still many inevitable adverse effects, such as multi-drug resistance, limiting therapeutic efficacy [ 8 ]. Immunotherapeutic agents have yielded promising results by not only treating primary cancer but by preventing distant metastasis and lowering the rate of recurrence [ 10 ]. Nevertheless, autoimmune disease is a major side effect of immunotherapy. Additionally, studies and shreds of evidence suggest that immunotherapy is less effective against solid tumors than lymphoma [ 11 ]. These cancers create an unusual extracellular matrix (ECM) which is quite challenging for immune cells to infiltrate [ 12 ]. These newly evolved targeted therapies and immunotherapies interfere with signaling pathways that are vital in malignant behaviors and normal homeostatic functions of the epidermis and dermis and cause dermatologic adverse events (dAEs) [ 13 ].

Considering all of these details, the demand for the advancement of novel strategies for seeking precise therapy of cancer has gained momentum in recent years. Recent efforts have been made to address the limitations of existing therapeutic approaches using nanoparticles. Nanoparticle-based drug delivery systems have reflected benefits in cancer treatment and management by demonstrating good pharmacokinetics, precise targeting, reduced side effects, and drug resistance [ 14 , 15 ].

On the heels of the advancements of nanotechnology, a number of nanotherapeutic drugs have been commercialized and are widely marketed, and many more have entered the clinical stage since 2010. Nanotherapeutic drugs have made progress in the domain of drug delivery systems and anti-tumor multidrug resistance (MDR) by providing a chance for drug combination therapy and inhibition of drug resistance mechanisms [ 16 ]. The pioneer effort was made to apply nanotechnology in medicine at ETH Zurich in the 1960s [ 17 ]. This combination has proved to be a better amalgamation in developing various diagnostic devices and better therapies. This review mainly focuses on basic principles of the application of nanotherapeutics, current challenges prospects, and describes the path of future research.

Nanoparticles

Nanoparticles (NPs) are technically defined as particles with one dimension less than 100 nm with unique properties usually not found in bulk samples of the same material [ 18 ]. Depending on the nanoparticle’s overall shape, these can be classified as 0D, 1D, 2D or 3D [ 19 ]. The basic composition of nanoparticles is quite complex, comprising the surface layer, the shell layer, and the core, which is fundamentally the central portion of the NP and is usually termed as the NP itself [ 20 ]. Owing to their exceptional features like high surface: volume ratio, dissimilarity, sub-micron size, and enhanced targeting system, these materials have gained a lot of importance in multidisciplinary fields.

NPs are found to have deep tissue penetration to increase enhanced permeability and retention (EPR) effect. Besides, the surface characteristics impact bioavailability and half-life by effectively crossing epithelial fenestration [ 21 ]. For example, NPs coated with polyethylene glycol (PEG), a hydrophilic polymer, decrease opsonization and circumvent immune system clearance [ 22 ]. Additionally, it is possible to optimize the release rate of drugs or active moiety by manipulating particle polymer characteristics. Altogether, the distinct properties of NPs regulate their therapeutic effect in cancer management and treatment.

Synthesis of NPs

The NPs are of different shapes, sizes, and structures. To achieve this, numerous synthesis methods are adopted. These methods can be largely categorized into two major groups: 1) bottom-up approach and 2) top-down approach. These approaches can be further classified into different subclasses based on reaction conditions and operation (Fig.  2 ).

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Classification of NP synthesis a top-down and b bottom-up approaches

Bottom-up Approach

This method involves building material from atoms to clusters to NPs, i.e., building from simpler substances, hence known as constructive method [ 23 ]. Some commonly used methods are spinning, solgel synthesis, chemical vapor deposition (CVD), plasma or flame spraying synthesis, laser pyrolysis, and biosynthesis.

Top-Down Approach

It is also known as the destructive method, which reduces bulk material or substance to synthesize NPs. A larger molecule is broken down or decomposed into smaller units that are converted into NPs [ 24 ]. It includes techniques such as mechanical milling, nanolithography, chemical etching, laser ablation, sputtering, electro-explosion, and thermal decomposition.

Remarkably, the morphological parameters such as size, shape and charge of NPs can be modified by changing the reaction conditions and other synthesis parameters [ 25 ]. Besides, the growth mechanism also determines the chemical properties of NPs. Hence understanding the growth mechanism is essential to synthesize required NPs.

Mechanisms of Cellular Targeting

For effective cancer therapy, it is essential to develop or engineer a drug or gene delivery system that has an excellent ability to target tumor cells sparing the normal healthy cells. It enhances therapeutic efficacy, thereby shielding normal cells from the effect of cytotoxicity. It can be achieved by the well-organized delivery of NPs into the tumor microenvironment (TME), indirectly targeting cancer cells. These nanoformulations should pass through numerous physiological and biological barriers. These barriers are complex systems of several layers (epithelium, endothelium, and cellular membranes) and components (mechanical and physicochemical barriers and enzymatic barriers). These facts impose specifications with respect to the size, biocompatibility, and surface chemistry of NPs to prevent unspecific targeting. However, mere cytosolic internalization of an NP drug molecule does not mean it reaches its subcellular target. Specific engineering and optimization are mandatory to enable cellular or nuclear targeting.

Several studies have been carried out so far and several more are in progress to discover NP-based drug targeting design. These nanocarriers typically should possess certain fundamental characteristics such as 1) ability to remain stable in the vascular system (blood) until they reach their target, TME, 2) to escape the reticuloendothelial system (RES) clearance, 3) escape mononuclear phagocyte system (MPS), 4) accumulate in TME via tumor vasculature, 5) high-pressure penetration into the tumor fluid, and 6) reach the target and only interact with tumor cells [ 26 ]. The vital aspects such as surface functionalization, physicochemical properties, and pathophysiological characteristics regulate the process of NP drug targeting.

Generally, NPs considered apt for cancer treatment have a diameter range of 10–100 nm. In order to understand the process of interaction and crosstalk between NP carriers and cancer cells and tumor biology, it is important to address the targeting mechanisms. The targeting mechanisms can be broadly classified into two groups, passive targeting and active targeting.

Passive Targeting

The observation of preferential accumulation of few macromolecules in cancer cells was found in the late 1980s. The first macromolecule to be reported to accumulate in the tumor was poly(styrene-co-maleic acid)-neocarzinostatin (SMANCS) by Matsuura and Maeda [ 27 ]. On further studies, this preferential distribution was attributed to the occurrence of fenestrations that are found in the damaged tumor blood vessels and to the poor lymphatic drainage, the amalgamation of which is known as “enhanced permeation and retention effect.”

Under certain conditions such as hypoxia or inflammation, the endothelium layer of the blood vessels becomes more permeable [ 28 ]. Under hypoxia situations, the rapidly growing tumor cells tend to put in action more blood vessels or engulf the existing ones to cope up. This process is known as neovascularization. These new blood vessels are leaky as they have large pores that lead to poor perm-selectivity of tumor blood vessels compared to the normal blood vessels [ 29 , 30 ]. These large pores or fenestrations range from 200 to 2000 nm depending on the cancer type, TME and localization [ 31 ]. This rapid and defective angiogenesis provides very little resistance to extravasation and permits NPs to diffuse from such blood vessels and ultimately collect within cancer cells.

In normal tissues, the drainage of ECF (extracellular fluid) into lymphatic vessels frequently happens at an average flow velocity of 0.1–2 µm/s, which maintains constant drainage and renewal [ 32 ]. When a tumor is formed, the lymphatic function gets derailed, which results in minimal interstitial fluid uptake [ 33 ]. This feature contributes to the NPs retention as they are not cleared and hoard in the tumor interstitium. This process denotes the enhanced retention part of the EPR effect. This exceptional feature does not apply to molecules with short circulation time and gets washed out rapidly from the cancer cells. Hence, to improve such situations, encapsulating these small molecules in nanosized drug carriers is routinely carried out to enhance their pharmacokinetics, provide tumor selectivity and reduce side effects [ 34 ].

Over the EPR effect, TME is a vital feature in passive targeting. One of the important metabolic features of rapidly proliferating tumor cells is glycolysis. It is the chief energy source for cell division [ 35 ] and makes the surrounding environment acidic. This lowered pH of TME can be exploited to use pH-sensitive NPs that release drugs at low pH [ 36 ].

This type of tumor-targeting is termed as “passive.” Passive targeting mainly relies on different tumor biology (vascularity, leakiness) and carrier characteristics (size and circulation time). This type of tumor-targeting does not possess a specific ligand for certain types of tumor cells. The EPR effect greatly relies on the fundamental tumor biology, such as 1) the degree or extent of angiogenesis and lymphangiogenesis, 2) the extent or degree of perivascular tumor invasion, and 3) intratumor pressure. These factors, combined with physicochemical characteristics of NPs, determine the efficiency of NP drug delivery system (Fig.  3 ).

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Passive cellular targeting

Examples of Passive Targeting

Taxanes are one of the most successful drug groups that are used in cancer treatment. Paclitaxel has shown great potency against a broad range of cancers. Breast cancer, lung cancer (small cell and non-small cell), and ovarian cancer are the most treated histologies with taxanes. US-FDA, in 2005, approved Abraxane® (albumin-bound paclitaxel, Abraxis Bio-Sciences), which is used for advanced or metastatic breast cancer (MBC).

Abraxane® is an anti-microtubule drug that stabilizes the microtubules by preventing depolymerization. It occurs when the drug encourages the microtubule assembly from tubulin dimers. This gained stability hinders microtubules reorganization, which is very important during interphase and mitotic cellular functions. During cell cycle and mitosis, paclitaxel, a well-used taxane, triggers unusual microtubules array along with multiple asters, respectively. Abraxane® alone or combined with another cytotoxic agent such as gemcitabine diminishes pancreatic stroma in pancreatic cancer xenograft mouse models [ 37 ].

Genexol PM® is an innovative nanoformulation of paclitaxel and sterile lyophilized polymeric micellar formulation without CrEL. Genexol PM®, according to trials, was found to have a three-times higher maximum tolerated dose (MTD) in nude mice. Besides, the biodistribution exhibited two- to three-times higher levels in different tissues such as liver, spleen, kidney, and lung and more prominently in cancer cells. It has been approved in South Korea to treat MBC. It is still under phase II clinical study in the USA to treat pancreatic cancer [ 38 ].

DaunoXome® (liposomal daunorubicin; Gilead Science/Diatos) is an anticancer medicine that reduces tumor cell growth. The active substance is daunorubicin. It is a unique formulation of daunorubicin (in liposome form) used to treat Kaposi’s sarcoma, a form of cancer that affects the skin, lungs, and intestines. US-FDA approved this in 1996 [ 39 ].

Although neovascularization and angiogenesis influence NP diffusion, it leads to greater interstitial pressure, which inhibits the accumulation of NPs. Moreover, due to heterogenous blood supply, the growth of the tumor cells is irregular, i.e., the cells that are close to blood vessels divide faster than those that are away from the blood vessel or deep in the core-forming hypoxic or necrotic area within the tumor. This irregular leaking, which causes high interstitial pressure, impedes drug delivery and accumulation and slows down the neovascularization process [ 34 ]. However, it is possible to control EPR effect, either mechanically or chemically. These include nitric oxide, peroxynitrate, bradykinin, VPF (vascular permeability factor), ultrasound, radiation, hyperthermia, etc. However, there are certain limitations and contra-indications.

Active Targeting

Active targeting depends on specific ligands or molecules, like transferrin and folate, which binds to molecules or receptors that are specifically expressed or over-expressed on the target cells (diseased organs, tissues, cells or subcellular domains) [ 40 ]. This type of targeting is called ligand-mediated targeting [ 41 ]. Here, the NPs that possess ligand with specific functions such as retention and uptake need to be in the target's proximity so that there is greater affinity. This strategy enhances the changes of NPs binding to the cancer cell, enhancing the drug penetration. The foremost indication of the same was observed in 1980 with antibodies grafted in the surface of liposomes [ 34 ], followed by other various types of ligands like peptides, aptamers. Hence, the main method is intended at increasing the crosstalk between NPs and the target without fluctuating the total biodistribution [ 42 ]. The vital mechanism of active targeting or ligand-mediated targeting is ligand identification by the target substrate receptors. The illustrative ligands may include proteins, peptides, antibodies, nucleic acids, sugars, small molecules like vitamins, etc. [ 43 ]. The most commonly studied receptors are transferrin receptor, folate receptor, glycoproteins and the epidermal growth factor receptor (EGFR). Ligand-target interaction triggers infolding of the membrane and internalization of NPs via receptors-mediated endocytosis. There are various mechanisms by which active targeting takes place. The majority of tumor-targeting is done by the tumor cell targeting in general by NPs. This process improves cell penetration. As stated before, transferrin is one of the widely studied receptors. It is a type of serum glycoprotein that aids in transporting iron into cells. These receptors are found to be overexpressed in most tumor cells, especially solid tumors and are expressed at lower levels in healthy cells. Hence, we can modify the NPs with associated ligands that specifically target transferrin [ 44 ]. For instance, A2780 ovarian carcinoma cells overexpress transferrin. This feature is used by transferrin-modified PEG-phosphatidyl-ethanolamine (Tf-Mpeg-pe) NPs that specifically target such cells [ 45 ]. Another alternative method is to target cells adjacent to cancer cells, such as angiogenic endothelial cells. These cells also have close contact with tumor blood vessels. This strategy makes it possible to create hypoxia and necrosis by reducing the blood supply to the cancer cells. It has been found out that tumor tissues are more acidic than normal ones. This has been extensively explained by the Warburg effect [ 46 ]. This explains the shift of cancer cell metabolism into glycolysis, forming lactic acid. When the lactic acid accumulates, the cell dies. To cope with this situation, the cells start overexpressing proton pumps that pump out excess lactic acid into the extracellular environment, making it more acidic. Therefore, liposome-based pH-sensitive drug delivery system has been studied.

The multivalent nature of the NPs improves the crosstalk of ligand coated NPs with target cancer cells. The design of such NPs is complex as NP architecture and ligand-target chemistry influence the efficacy of the entire method. Other factors such as route of administration, physicochemical properties such as ligand density [ 47 ], and size of NPs [ 8 ] contribute to the system's success (Fig.  4 ).

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Pictorial representation of active cellular targeting

Examples of Active Targeting

EGFR, a member of the ErbB family of tyrosine kinase (TK) receptors, is overexpressed in various types of cancer, especially with squamous cell histology. Gold NPs with anti-EGFR-PEG-AuNPs and anti-IgG-PEG-Au nanoparticles can be used to target the human SCC [ 48 ].

Herceptin® is a therapeutic drug that targets human EGF receptor-2 (HER2) that is overexpressed on breast cancer cell surfaces. HER2-targeted PEGylated liposomal doxorubicin was developed to reduce cardiotoxicity, a known side effect of anthracyclines [ 49 ].

The surface of the tumor endothelium expresses a glycoprotein known as vascular cell adhesion molecule-1 (VCAM-1) that is involved in the process of angiogenesis. A study has highlighted NPs that target VCAM-1 in the breast cancer model, indicating its potential role [ 50 ].

Folic acid, also known as vitamin B9, is vital in nucleotide synthesis. Folic acid is internalized by the folate receptor that is expressed on the cells. However, tumor cells overexpress FR-α (alpha isoform of folate receptor), while FR-β is overexpressed in liquid cancer cells [ 51 ]. Targeting the folate receptors by NPs has been currently for specific cancer treatments [ 52 , 53 ].

Nanoparticles in Cancer Therapy

NPs used extensively in drug delivery systems include organic NPs, inorganic NPs, and hybrid NPs (Fig. ​ (Fig.5 5 ).

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Various types of nanomaterials used in cancer therapy

Organic Nanoparticles

Polymeric nanoparticles.

Polymeric nanoparticles (PNPs) are well-defined as “colloidal macromolecules” with specific structural architecture formed by different monomers [ 54 ]. The drug is either entrapped or attached to NPs’exterior, creating a nanosphere or a nanocapsule to achieve regulated drug release in the target [ 55 ]. Initially, PNPs were made up of non-biodegradable polymers such as polyacrylamide, polymethylmethacrylate (PMMA), and polystyrene [ 56 ]. However, the accumulation of these led to toxicity due to difficulty in eliminating these from the system. Biodegradable polymers such as polylactic acid, poly(amino acids), chitosan, alginate, and albumin are now being used and are known to reduce toxicity and enhance drug release and biocompatibility [ 57 ]. Proven research has reflected that by coating PNPs with polysorbates and by using polysorbates surfactant effect. Exterior coating enhances NPs' interactions with the endothelial cell membrane of the blood–brain barrier (BBB) [ 58 ].

A study showed that nanocapsules loaded with indomethacin involved a substantial decrease in the size of the tumor and improved survival in a xenograft glioma model in rats [ 59 ]. This is a growing field with more than ten polymeric NPs containing anticancer drugs are under clinical development. A few examples include paclitaxel poliglumex (Xyotax), PEG-camptothecin (Prothecan), Modified dextran-camptothecin (DE 310), HPMA copolymer-DACH-platinate (AP5346), HPMA copolymer-platinate (AP 5280), HPMA copolymer-paclitaxel (PNU166945), and HPMA copolymer-doxorubicin galactosamine (PK2) [ 60 ].

Dendrimers are spherical polymeric macromolecules with defined hyperbranched architecture. Highly branched structures are the characteristic feature of dendrimers. Typically, the synthesis of dendrimers is initiated by reacting an ammonia core with acrylic acid. This reaction results in forming a “tri-acid” molecule that further reacts with ethylenediamine to yield “tri-amine,” a GO product. This product further reacts with acrylic acid to give rise to hexa-acid, which further produces “hexa-amine” (Generation 1) product and so on [ 61 ]. Typically, the size of the dendrimers ranges from 1–10 nm. However, the size may reach up to 15 nm [ 62 ]. Given their specific structure like defined molecular weight, adjustable branches, bioavailability, and charge, these are used to target nucleic acids. Some dendrimers that are widely used are polyamidoamine (PAMAM), PEG (poly(ethyleneglycol)), PPI (polypropylenimine), and TEA (triethanolamine) [ 63 ].

A PAMAM dendrimer was initially designed to achieve MDR management. DNA assembled PAMAM dendrimers have been described extensively. As compared with animals treated with single-agent chemotherapy, the synthesized dendrimers significantly delayed the growth of epithelial cancer xenografts [ 64 ].

mAb Nanoparticles

Monoclonal antibodies are widely used in cancer treatment for their particular targeting abilities [ 65 ]. These mAb are now combined with NPs to form antibody–drug conjugates (ADCs). These are proved to be highly specific and compelling than cytotoxic drugs or mAb alone. For instance, an antibody–drug NP consisting of paclitaxel core and a surface modified with trastuzumab presented a better anti-tumor efficacy and lower toxicity than single-agent paclitaxel or trastuzumab alone in HER2 positive breast epithelial cell control [ 66 ].

Extracellular Vesicles

Extracellular vesicles (EVs) are double-layered phosphor-lipid vesicles ranging from 50–1000 nm n size [ 67 ]. EVs are continuously secreted by different cells types and vary in origin, size, and composition. EVs are divided into three classes: 1) exosomes, 2) microvesicles, and 3) apoptotic bodies [ 68 ]. NPs combined with exosomes are widely used as they have lipid and molecules that are very similar to origin cells. Besides, they escape the immune surveillance and internalize very quickly within the cancer cells. They act as natural vehicles by delivering cytotoxic drugs and other anti-tumor drugs to the target sites. Exosomes loaded with doxorubicin (exoDOX) are the best example. exoDOX is used to treat breast cancer and has shown great results compared to conservative treatment with doxorubicin by enhancing the cytotoxicity and avoiding cardiotoxicity [ 69 ]. Exosome NPs have intrinsic biocompatibility features, advanced chemical stability, and intracellular communications compared to synthetic NPs. Nevertheless, drawbacks like deficiency of standard conditions for exosomal isolation and purification are crucial and need to be addressed [ 70 , 71 ].

These are spherical vesicles comprising phospholipids that may be either uni-lamellar or multi-lamellar to encapsulate drug molecules [ 72 ]. Liposomes are unique in having characteristics such as low intrinsic toxicity, weak immunogenicity, and biological inertness [ 73 ]. Liposomes are the first nanoscale drug that was approved in 1965 [ 74 ]. A typical liposome structure is composed of a “hydrophilic core” and a “hydrophobic phospholipid bilayer.” This unique architecture makes it possible for them to entrap both hydrophilic and hydrophobic drugs to effectively protect the entrapped drug from environmental degradation in circulation [ 75 ].

Liposomes provide an excellent platform for drug delivery such as doxorubicin, paclitaxel, and nucleic acid as well by demonstrating higher anti-tumor efficacy and enhanced bioavailability [ 76 ]. Doxil® and Myocet® are approved liposome-based formulations of daunorubicin used to treat MBC [ 77 , 78 ]. However, due to shortcomings like decreased encapsulation efficacy, speedy removal by MP, cell adsorption, and short shelf life, the application of liposome-based NPs is limited.

Solid Lipid Nanoparticles (SLN)

They are colloidal nanocarriers (1–100 nm) made up of a phospholipid monolayer, emulsifier, and water [ 79 ]. These are known as zero-dimensional nanomaterials. The lipid component may be triglycerides, fatty acids, waxes, steroids, and PEGylated lipids [ 80 ]. Unlike conventional liposomes, SLNs have a “micelle-like structure” within which the drug is entrapped in a non-aqueous core. Examples include mitoxantrone-loaded SLN, which has shown reduced toxicity and enhanced bioavailability [ 81 ]. The incorporation of doxorubicin and idarubicin by SLN in “P388/ADR leukemia cells” and the “murine leukemia mouse model” has shown positive results [ 82 ].

Nanoemulsions

Nanoemulsions are colloidal NPs with heterogeneous mixtures of an oil droplet in aqueous media ranging from 10–1000 nm [ 83 ]. Three representative types of nanoemulsions can be made in: 1) oil-in-water system, 2) water-in-oil system, and 3) bi-continuous nanoemulsions. Membrane-modified nanoemulsions have been extensively studied. For instance, nanoemulsions loaded with spirulina and paclitaxel showed an improved anti-tumor effect by regulating immunity through TLR4/NF-kB signaling pathways [ 84 ]. Nanoemulsion consisting of rapamycin, bevacizumab, and temozolomide is known to treat advanced melanoma [ 85 ]. Nanoemulsions are different from liposomes and certainly have enhanced characteristics than others, such as optical clarity, stability, and biodegradability [ 86 ]. However, there are challenges to clinical applications of these nanoemulsions as these involve high temperature and pressure and instruments such as homogenizers and microfluidizers that are expensive.

Cyclodextrin Nanosponges

Cyclodextrins are usually used as stabilizers to increase the drug loading capacity of NPs [ 87 ]. Nanosponges are tiny, mesh-like structures [ 88 ]. Β-cyclodextrin nanosponges loaded with paclitaxel have shown sound cytotoxic effects in MCF-7 cell line culture [ 89 ]. Similarly, camptothecin has shown improved solubility and stability when formulated with cyclodextrin-based nanosponges [ 90 ].

Inorganic Nanoparticles

Carbon nanoparticles.

Carbon NPs as the name suggests are based on the element carbon. They have been widely utilized in medical arenas because of their optical, mechanical, and electronic properties combined with biocompatibility [ 91 ]. Due to their inherent hydrophobic nature, carbon NPs can encapsulate drugs through π-π stacking [ 92 ]. Carbon NPs are further categorized into graphene, carbon nanotubes, fullerenes, carbon nanohorns, and graphyne. Although all these are carbon-based, they vary in their structure, morphology, and properties.

“Graphene” is 2D crystal with sp2-hybridized carbon sheet that holds extraordinary mechanical, electrochemical, and high drug loading properties. Further, based on composition, properties, and composition, graphene can be divided as follows: 1) single-layer graphene, 2) graphene oxide (GO), 3) reduced graphene oxide (rGO), and 4) multi-layer graphene [ 93 ]. GO and rGOs are widely used due to their ability to target hypoxia [ 94 ] and irregular angiogenesis in TME [ 95 ]. Studies have shown that GO-doxorubicin exhibits higher anticancer activities in cellular models of breast cancer [ 96 ].

Fullerenes are large carbon-cage molecules composed of carbon allotrope with different conformation types such as sphere, ellipsoid, or tube. They are the most widely studied nanocarriers as they have typical structural, physical, chemical, and electrical properties [ 97 ]. These are used in photodynamic therapy as they have triple yield and generate oxygen species due to the presence of extended π-conjugation and the ability to absorb light [ 98 ]. PEG-modified fullerenes showed promising photodynamic effects on tumor cells [ 99 ].

Carbon nanotubes (CNTs) are cylindrical tubes, most often considered as rolls of graphene, were discovered in the late 1980s. They are classified into two groups: 1) single-walled CNTs and 2) multi-walled CNTs. As they are carbon-based, they can bring upon immune response by interacting with immune cells, thereby suppressing the tumor growth. Traditionally, they have been used as DNA delivery vectors and for thermal ablation therapy. For instance, a fluorescent single-walled CNT with mAb encapsulating doxorubicin is used to target colon cancer cells. Such CNTs form a complex which is effectively engulfed by the cancer cells leading to the intracellular release of doxorubicin, whereas the CNTs are retained in the cytoplasm [ 100 ].

Quantum Dots

Quantum dots are typically nanometer-scale semiconductors with a broad spectrum of absorption, narrow emission bands, and high photostability, allowing them to be widely used in biological imaging [ 101 ]. Based on carbon, these are divided into: 1) graphene quantum dots, 2) nanodiamond quantum dots, and 3) carbon quantum dots. Besides biological imaging, quantum dots are being actively investigated in cancer treatment. The most commonly used quantum dots is graphene quantum dots due to their inherent biocompatibility and rapid excretion. For example, quantum dots aptamer—doxorubicin conjugate targets prostate cancer cells [ 102 ]. However, the deficiency of optimized process in producing quantum dots is the major obstacle.

Metallic Nanoparticles

Metallic nanoparticles are commonly explored in “biological imaging” and targeted DDS due to their remarkable optical, magnetic, and photothermal properties. Some of the most commonly used metallic NPs are gold NPs, silver NPs, iron-based NPs, and copper NPs. Gold NPs are used as intracellular targeting drug carriers because the size and surface properties are easily controlled [ 103 ]. Moreover, their visible light extinction behavior makes it possible to track NP trajectories in the cells. “Anti-HER2 functionalized gold-on-silica nanoshells” have been shown to aim HER2 positive breast cancer cells [ 104 ]. Combidex®, an iron oxide NP formulation, is presently in the late-stage clinical testing phase to detect nodal metastases [ 105 ]. Feraheme®, a ferumoxytol containing iron oxide NP formulation, is used to treat iron-deficiency anemia. This is also used to treat nodal metastases in prostate and testicular cancer and was approved by FDA in June 2009 [ 106 , 107 ].

Magnetic Nanoparticles

Magnetic NPs are generally used in MRI imaging, and drug delivery contains metal or metal oxides. These are usually covered with organic substances like polymers and fatty acids to enhance stability and biocompatibility [ 108 ]. LHRH-conjugated superparamagnetic iron oxide NPs are effective in targeting and imaging of breast cancer [ 109 ]. Moreover, magnetic NPs are used in magnetic hyperthermia for thermal ablation of cancer cells [ 110 , 111 ]. Some of the magnetic NPs that are in the market or in the clinical trial phase are Feridex® and Resovist® for liver metastasis and colon cancer [ 112 ].

Calcium Phosphate Nanoparticles

“Calcium phosphate NPs” is biologically compatible, biodegradable, and do not cause any harsh adverse reactions. Hence, they are used as a delivery agent for insulin, growth factors, antibiotics, and contraceptives [ 113 ]. They are also used in the delivery of oligonucleotides and plasmid DNA [ 114 ]. Calcium phosphate NPs combined with either viral or non-viral vector has been positively used as delivery vectors in cellular gene transfer. A “liposomal nanolipoplex formulation” of calcium and glycerol has shown decreased toxicity and enhanced transfection features [ 115 , 116 ].

Silica Nanoparticles

Silica being a significant component of many natural materials was only studied concerning biology recently. Silica NPs are commonly used to deliver genes by functionalizing the NP surface with amino-silicanes [ 117 ]. N-(6–aminohexyl)–3–aminopropyl–trimethoxysilane functionalized silica NPs have shown excellent efficiency in the transfection of Cos-1 cells with minimal toxicity and is now commercially available [ 118 ]. Mesoporous silica NPs are considered one of the best drug carriers due to their better pharmacokinetic properties. They have been extensively used in immunotherapy. According to a study, colorectal cancer cells have shown successful uptake of camptothecin-loaded mesoporous silica NPs.

Mechanism of NPs in Overcoming Drug Resistance

Drug resistance is one of the chief problems in cancer therapy and management. It prevails across all types of cancer and all possible treatment modalities. Drug resistance is a phenomenon that results when diseases become tolerant to pharmaceutical treatments. Drug resistance can be classified into two types: 1) innate and 2) acquired [ 119 ]. Innate resistance usually results from pre-existing mutations in the genes that are involved in cell growth or apoptosis. Acquired resistance is defined as the type of resistance that is developed after a particular anti-tumor treatment, which may result from the development of new mutations or from alterations in the TME during treatment. Nanoparticles, due to their extraordinary ability to co-encapsulate multiple therapeutic agents, can also be used to overcome cancer-related drug resistance.

Targeting Efflux Transporters

Efflux transporters are classified under the family of “ATP-binding cassette (ABC) transporters.” These have a significant role in MDR. The primary function of these transporters is to pump out drugs out of the cell and reduce the concentration. “P-glycoprotein (P-gp)” is one such efflux transporter that is overexpressed by drug-resistant cancer cells [ 120 , 121 ].

Overexpression of P-gp has been linked with inadequate treatment response, especially in breast cancer [ 122 ] and ovarian cancer [ 123 ]. NPs can be used to tackle efflux pumps. As NPs internalize the cell via “endocytosis” instead of diffusion and release the drug at the “perinuclear site,” which is distant from active efflux pumps, NPs can bypass the efflux pumps [ 124 ]. Besides, by modifying the control of drug releases, such as by utilizing low pH levels and redox as triggers, NPs can effectively bypass efflux pumps [ 125 , 126 ].

Combination therapy is yet another method to overcome MDR. NPs can be loaded with multiple drugs within a single drug carrier [ 127 ]. Inhibiting efflux transporter expression instead of just dodging them would be another viable option. This can be achieved by building NPs in such a way that it can entrap both efflux pump inhibitors and chemotherapy agents [ 128 ]. A recent study positively reflected upon reversing MDR in breast cancer cells by using NPs that co-deliver COX-2 inhibitors and doxorubicin [ 129 ]. Similarly, using silica NP that encapsulates miRNA-495 and doxorubicin has proved effective in overcoming drug resistance in lung cancer cells [ 130 ]. Another interesting study found out that using NPs in the tumor neo-vasculature targeting KDR receptors is a more effective anti-tumor function than P-gp inhibitor combination therapy. Yet, another way of overcoming drug resistance is by depleting the source of ATP, which is essential for the functioning of ABC transporters. This can be done by targeting mitochondria which leads to a decrease in ATP production.

Targeting an Apoptotic Pathway

Cancer cells proliferate due to faulty apoptotic machinery and upsurge their survival adding to drug resistance [ 131 ]. The faulty apoptotic pathway gets activated by “deregulation of Bcl-2” and “nuclear factor kappa B (NF-κB).” These are the most widely investigated anti-apoptotic proteins and can be potentially used as the target for reversing drug resistance. Using a classic process of co-delivery of “Bcl-2 siRNA and chemotherapeutics” by NPs is a way to overcome MDR [ 132 ]. NF-κB inhibitors have been used in combination with “pyrrolidine dithiocarbamate (PDTC)” [ 133 ] and curcumin [ 134 ]. Besides suppressing anti-apoptotic factors, triggering pro-apoptotic factors is another to fight “apoptotic pathway-mediated drug resistance.” For instance, a combination of ceramide and paclitaxel is a good example [ 135 ]. Ceramide restores the expression of a chief tumor suppressor, p53 protein, by regulating alternative pre-mRNA splicing. Delivering ceramide via NPs is an excellent way to correct the p53 missense mutation [ 136 ]. Owing to its potential, a combination of ceramide and paclitaxel has shown significant therapeutic efficacy in cancer drug resistance models. Transfecting the p53 gene by cationic SLNs has been reported in lung cancer cases [ 137 ]. Similarly, transfecting the p53 gene by PLGA has been carried out in breast cancer cells models that have shown potent induction of apoptosis and inhibition of tumor growth [ 138 ].

Some NP-based DDS act by impeding efflux pumps and encouraging apoptosis [ 139 ]. A pioneering study conducted to prove both pump- and non-pump-mediated drug resistance used an “amphiphilic cationic NP” entrapping paclitaxel and Bcl-2 converter gene in drug-resistant liver cancer models. NP complex diminished P-gp-induced drug efflux and the apoptosis activation. Similarly, co-delivery of “doxorubicin and resveratrol encapsulated in NPs” has shown noteworthy cellular toxicity on doxorubicin resistance breast cancer cells by downregulating the expression of Bcl-2 and NF-κB, thereby initiating apoptosis as well as through the inhibition of efflux transporter expression [ 140 ]. A similar study was done on multi-drug resistant prostate cancer cells by using folic acid-conjugated planetary ball milled NPs encapsulated with resveratrol and docetaxel. This worked by downregulating anti-apoptotic gene expression while inhibiting ABC transporter markers [ 141 ].

Targeting Hypoxia

Hypoxia is yet an additional aspect that backs MDR [ 142 ]. Due to abnormal blood vessels in the vicinity of the tumor and due to the increasing demand of oxygen by the rapidly growing tumor, some tumor cells are repeatedly in a hypoxic condition. The part of the tumor that is in hypoxic condition often escapes from the chemotherapy drugs. Hypoxia creates an oxygen ramp inside the tumor that intensifies tumor heterogeneity, encouraging a more aggressive phenotype. Moreover, the hypoxia condition has been established to facilitate the overexpression of efflux proteins [ 143 ]. The major protein, “hypoxia-inducible factor 1α (HIF-1α)” acts an important role. Hence targeting HIF-1α or silencing HIF-1α gene is a way to overcome drug resistance. NPs containing HIF-1α siRNA can be used to reduce hypoxia-mediated drug resistance [ 144 ]. Instead of directly targeting HIF-1α, indirect inhibition of HIF-1α signaling can be used. For example, the “PI3K/Akt/mTOR pathway” is known to control the expression of HIF-1α. Inhibition of this pathway effectively downregulates the expression of HIF-1α, which enhances the sensitivity of MDR cells to cancer treatment [ 145 ]. NPs like PLGA-PEG and PEGylated and non-PEGylated liposomes can be used effectively. In addition, “heat shock protein 90 (HSP90)” is needed for transcriptional activity of HIF-1 and inhibition of HSP90, which downregulates the expression of HIF-1α [ 146 ]. The HSP90 inhibitor in “17AAG loaded NPs” has dramatically improved MDR in bladder cancer treatment [ 147 ].

Nanoparticles and Proteomics

When NPs are subjected to the biological system, they are surrounded by cellular and serum proteins which form a structure known as protein corona (PC) [ 148 ]. Based on the degree of interaction of these proteins with the NPs, there are classified into the hard corona and soft corona. “Hard corona” is formed when these proteins have a high binding affinity towards the NPs. “Soft corona” is produced when these proteins are loosely bound to the NPS. It has been established that the most protein forming a PC first will be eventually substituted by proteins with higher affinities. This is known as Vroman effect [ 149 ]. Hence developing the technology that can manufacture NPs with desired properties is essential. Several proteomic approaches such as MS, LC–MS, SDS-PAGE, isothermal microcalorimetry (ITC), etc. [ 150 ], are being used. PC affects the crosstalk of NP with the biological setting and thereby governs the application and usage of the same in the medical field.

Cancer proteomics studies the number of proteins in cancer cells and serum, which supports hunting proteins and biomarkers that aids in diagnosis, treatment, and prognosis [ 151 ]. It also helps in understanding cancer pathogenesis and drug resistance mechanism. Post-translational modifications (PTMs) play an indispensable part in occurrence, recurrence, and metastasis. Besides using chemotherapy and kinase inhibitors, novel agents like siRNA, mRNA, and gene editing are central therapeutics used with NPs.

Nanotechnology for Small Interfering RNA (siRNA) Delivery

siRNAs are small ds RNA molecules (around 21 nucleotides long) that suppress the expression of genes in the target. This process is known as “RNA interference.” A few siRNA-based NPs that are currently under clinical investigations are ALN-TTR01 that is used to target the transthyretin gene to treat transthyretin-mediated amyloidosis, and Atu027, which is a liposomal siRNA that targets protein kinase N3 and TKM-ApoB that knock downs the expression of ApoB [ 152 , 153 ].

Nanotechnology for Tumor microRNA Profiling and Delivery

MicroRNAs are a class of endogenous “single-stranded non-coding RNA” molecules that control post-transcription gene expression by blocking translation of the target mRNA or repressing protein production by destabilizing mRNA [ 154 ]. These are emerging as vital biomarkers that are a significant target for cancer diagnosis, therapy, and treatment. The base priming nature of nucleic acid forms the very foundation for nanotechnology used miRNA profiling techniques. Several profiling techniques use biosensors or surface plasmon resonance imaging techniques in combination with molecular biology enzymatic reactions. Nanotechnology can be used for the delivery of MicroRNAs. For example, biodegradable polycationic prodrugs showed promising results in the regulation of polyamine metabolism [ 155 ]. MicroRNA-loaded polycation-hyaluronic acid NPs of single-chain antibody fragments have shown progressive downregulation of “survivin expression” in high metastatic cancer load in the lung of murine B16F10 melanoma.

DNA Nanotechnology for Cancer Therapy

DNA-based nanostructures have been synthesized for DNA sensors to detect nucleic acid, DNA-coated gold NPs for lead sensing by hybridizing Pb-activated DNAzyme to the linking DNA, scaffolds to organize organics, inorganic, and biomolecules into distinct morphology molecular transporters, and drug delivery (Table ​ (Table1 1 ).

List of nanomedicines for cancer therapy approved by FDA [ 156 – 159 ]

Advantages of Nanoparticles in Cancer Therapy

The utilization of nanotechnology in the diagnosis, treatment, and management of cancer has led to a whole new era. NPs, either by active or passive targeting, augment the intracellular concentration of drugs while avoiding toxicity in the healthy tissue. The targeted NPs can be designed and altered as either pH-sensitive or temperature-sensitive to establish and regulate the drug release. The pH-sensitive drug delivery system can deliver drugs within the acidic TME. Similarly, the temperature-sensitive NPs release the drugs in the target site due to changes in temperature brought in by sources like magnetic fields and ultrasound waves. In addition, the “physicochemical characteristics” of NPs, such as shape, size, molecular mass, and surface chemistry, have a significant part in the targeted drug delivery system. Further, NPs can be modified according to the target and used to target a particular moiety.

Conventional chemotherapy and radiation therapy have several disadvantages concerning efficacy and side effects because of uneven dispersal and cytotoxicity. Therefore, cautious dosing is required that effectively kills cancer cells without any significant toxicity. To reach the target site, the drug has to pass several fortifications. Drug metabolism is a very complex process. In physiological conditions, the drug needs to pass TME, RES, BBB, and kidney infiltration. RES or macrophage system is made up of “blood monocytes, macrophages, and other immune cells” [ 160 ]. MPS in the liver, spleen, or lungs react with the drugs and activate “macrophages or leukocytes” that rapidly remove the drug. This leads to a short half-life of the drug [ 161 ]. To overcome this, NPs with “surface modification,” such as PEG, bypass this mechanism and increase the “drug half-life.” Besides, kidney infiltration is a crucial function in the human body. Proper kidney infiltration thus minimizes the toxicity caused by NPs.

The brain-blood barrier (BBB) is a specialized protection structure offered to protect the CNS from harmful and toxic agents. “Brain capillary endothelial cells” are arranged in the form of a wall that provides essential nutrients to the brain. Since the primary function of BBB is to block toxic agents to reach the brain, currently available chemotherapy agents for brain cancer are highly limited to intraventricular or intracerebral infusions [ 162 ]. However, NPs are known to cross BBB. Now, several approaches such as EPR effect, focused ultrasound, peptide-modified endocytosis, and transcytosis are used to deliver NPs. Glutathione PEGylated liposome encapsulated with methotrexate showed improved methotrexate uptake in rats [ 163 ]. Au-NPs are often used as they have proven to help transport drugs to induce apoptosis [ 164 ].

NPs being carriers also increase the drug stability by preventing the degradation of the encapsulated cargo. Additionally, a large volume of drugs can be encapsulated without any chemical reaction. Dry solid dosage forms are more stable than nanoliquid products [ 165 ]. Stabilizers can be used to enhance stability. Yet another way to increase stability is to use porous NPs.

Tumor has unique pathophysiology features such as extensive angiogenesis, flawed vascular architecture and defective lymphatic drainage. The NPs use these features to target tumor tissue. Due to reduced venous return in tumor tissue and meager lymphatic clearance, NPs are effectively retained. This phenomenon is known as EPR. Similarly, by targeting the adjacent tissues, tumor-targeting can be accomplished [ 166 ].

NPs can be administered through several routes like oral, nasal, parenteral, intra-ocular etc. NPs have a high surface-to-volume ratio and intracellular uptake. Studies have reported that NPs are more effective than microparticles as drug carriers [ 167 ].

Nanoparticles in Immunotherapy

The immune system sets an important part in the establishment and development of cancer cells. The advancement of immunotherapy has revolutionized cancer therapy. It is found that NPs not only help in target delivery of chemotherapy but can also be used in combination with immunotherapy. There are several approaches in immunotherapy aimed at activating the immune system against cancer cells [ 168 ] by “immune checkpoint blockade therapy,” “cancer vaccine therapy,” “chimeric antigen receptor (CAR)-T cell therapy,” and “immune system modulator therapy” [ 169 – 171 ]. NP-based immunotherapy includes “nanovaccines,” “aAPCs (artificial antigen-presenting cells),” and “immunosuppressed TME targeting.”

Nanovaccines specialize in delivering “tumor-associated antigens” and “adjuvants” to antigen-presenting cells, such as dendritic cells (DCs) [ 172 ]. Moreover, these can also be employed as adjuvants to enhance “APC antigen presentation” and promote DC maturation that leads to the stimulation of cytotoxic T cells that have anti-tumor function [ 173 , 174 ]. Liposomes, PLGA NPs, gold NPs are found to have the ability to deliver TAAs into DCs in the cytoplasm [ 175 ]. Mesoporous silica, the most used inorganic NP, has exhibited an adjuvant role, leading to immune response stimulation [ 176 ]. Artificial APCs interact with MHC-antigen complexes directly which binds to T cells. They also bind to co-stimulatory molecules that bind to co-stimulatory receptors leading to T cell activation [ 177 ]. Targeting the immunosuppressed TME is yet another method of using NPs in immunotherapies. This is done by targeting essential cell types in TME such as “tumor-associated macrophages (TAMs),” regulatory T cells, and “myeloid-derived suppressor cells (MDSCs).”

Besides, the combination of chemoimmunotherapy has been demonstrated to be a capable approach in cancer therapy. For instance, a study has shown that co-loading Nutlin-3a, which is a chemotherapeutic agent and cytokine GM-CSF, in “spermine-modified acetylated dextran (AcDEX) NPs” improved cytotoxic CD8( +) T cells proliferation and activated an immune response [ 178 ].

“Programmed cell death protein 1 (PD-1)” and “programmed cell death ligand 1 (PD-L1)” are some of the essential immune checkpoints [ 179 ]. Hence immune checkpoint inhibitors are used to target these using NPs. According to a study, conventional immune checkpoint inhibitors of PD-L1/PD-1 displayed inconsistent responses. To enhance the chances and bonding of immune checkpoint inhibitors and immune checkpoints, multivalent poly (amidoamine) dendrimers were used. Usage of these dendrimers not only showed enhanced PD-L1 blockade but also showed improved drug accumulation at the tumor site [ 180 ].

Nanoparticles in Cryosurgery

Cryosurgery is an advanced practice of freeze-destroying cancer tissue. Although this is less invasive and causes intraoperative bleeding and postoperative complications, certain drawbacks like inadequate freezing capacity and damage to adjacent cells need to be addressed [ 181 ]. The rise of nanotechnology has enabled the use of NPs in cryosurgery.

The primary working of nanocryosurgery is introducing NPs with particular properties into the cancer cells and causing freezing [ 182 ]. During this process, ice is formed within the cells, which causes damage to it. This is an important process and can be carried out effectively using NPs. The thermal conductivity property of NPs can be exploited, which significantly freeze the tumor tissue and cause tumor damage [ 183 ]. Besides, they cool down rapidly, and it is feasible to regulate the “growth direction” and “direction of the ice ball” (Fig.  6 ).

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Diagrammatic representation of NPs in cryosurgery

When the location of the tumor makes it not feasible for cryosurgery or if other adjacent organs are at risk, there are high chances that the freezing can damage healthy tissue. Recently, phase change materials (PMs) made up of NPs are used to protect the adjacent normal healthy tissue during cryosurgery [ 184 ]. For instance, liposome-based microencapsulated phase change NPs have shown incredible results in protecting surrounding healthy tissue [ 185 ]. These NPs are deemed to possess large latent heat and low thermal conductivity, making them perfect for cryosurgery.

Significant Challenges in the Clinical Application of Nanoparticles

At present, as nanotechnology has bloomed, the amount of knowledge and research put into nanoparticles has steeply raised. But only a few of them actually make it up to clinical trials. Most of them only halt at in vivo and in vitro stages. Each individual nanoformulation has particular challenges in their clinical translation, but most NPs face similar challenges that can be divided into biological, technological, and study-design related.

Biological challenges include lack of routes of administration, tempering biodistribution, the channel of NPs across the biological barriers, their degradation, and toxicity [ 186 ]. NPs are usually injected via intravenous injections directly into the blood, which takes away NPs, making it challenging to stay and interact with the target site. As a result, a high concentration drug is used, which might not provide desired therapeutic effects [ 187 ]. However, magnetic NPs can be used to overcome this as many in vivo and in vitro studies have proved the usage of 3D magnetic fields to control the movement of NPs against blood flow. But, the effect of magnetic fields on the human body, crosstalk between magnetic fields, and a large number of NPs has to be researched upon.

Controlling the biological fate of NPs is very hard and needs a lot of focus. Even though NPs are made up of biosafety materials and are modulated accordingly to increase the retention time and half-life, there runs a risk of lung, liver and kidney damage. Some factors that govern toxicity are surface area, particle size and shape, solubility, and agglomeration [ 188 ]. NPs have shown greater deposition in the lung with inflammatory, oxidative and cytotoxic effects [ 189 ]. Studies reveal that healthy cells often suffer from free radicals generated by NPs [ 190 ]. Fabricating NPs with more biocompatible substances like chitosan and materials that disintegrate after near infrared light irradiation may be potential solutions.

Another tricky challenge is avoiding the “mononuclear phagocytic system (MPS).” In biological fluids, NPs adsorb proteins to produce PC, which attacks MPS to uptake NPs. To escape this, NPs have been coated with materials that prevent the formation of the protein corona. However, they have not shown any significant results. Designing NPs that target “macrophages” and using those as new drug vehicles can be pitched to overcome this problem. Currently, preventing macrophage recruitment, depleting and reprograming TAMs, and obstructing “CD47-SIRPα pathways” are commonly used strategies [ 191 ].

Technological challenges of NPs include scale-up synthesis, equal optimization, and performance predictions. These are very crucial in safeguarding the clinical success of NPs. Most of the NPs that are used in vivo and in vitro studies are usually produced in minor batches, and scale-up for huge quantities is not constantly feasible given instrumentation and other reasons. The lead clinical candidates that prove to be the best in animal models are not systematically designed optimized. To overcome this, we can use certain methods that can test numerous nanoformulation and by selective iterations selecting a single optimized formulation [ 192 – 194 ]. However, such hits shouldn’t be introduced directly in human testing. Predicting nanoparticle efficacy and performance is hard and replicating the in vivo results in human trials is a herculean task. Computational or theoretical modeling along with experimental results can be designed to imitate physiological tissue and surrounding. For instance, organs-on-chips are being actively studied and can improve NP predictions of efficacy and performance.

Study-design challenges like study size, intent, and timing of NP therapies during the therapy impact significantly during clinical studies. Most of the studies revolve around “cell and animal models” that may not provide comprehensible results in human trials. Therefore, the usage of a single model is tough to imitate natural reactions in the human body. In addition, “models of cancer metastasis” should be actively researched as metastasis is one of the significant properties of cancer. Moreover, N  = 1 clinical studies will be required if we focus on personalized medicine. This needs to count in many factors such as genetic, environmental, and past medical history. [ 195 , 196 ]. Another major challenge is that NPs are never used as first-line therapies. Although we have effectively approved nanoformulations, they are usually saved for further treatment if disease progression is found in the clinical trial scenario. Most of the patients have either had progressed on multiple lines of therapies or have gained drug resistance. These situations often skew the clinical trial results and lessen the chance of NP treatment to benefit those who are likely still treatable.

Conclusion and Future Perspective

Nanotechnology has shown a promising new era of cancer treatment by delivering small molecules for cancer detection, diagnosis, and therapy. Cancer therapies based on the exceptional features of NPs are being vastly used in the clinical setting of several cancer types. NP-based DDS is linked with enhanced pharmacokinetics, biocompatibility, tumor targeting, and stability compared to conventional drugs. Moreover, NPs provide an excellent platform for combination therapy which helps in overcoming MDR. With increasing research, several types of NPs, such as polymeric NPs, metallic NPs, and hybrid NPs, have shown improved efficacy of drug delivery. Researchers must be well attentive to the features of the nominated nanoplatforms and the properties of therapeutic agents. However, there are certain limitations like deficiency of in vitro models that precisely replicate in vivo stage, immunotoxicity, the long-term toxicity, and neurotoxicity. Although “nanovaccines” and “artificial APCs” have proved improved efficacy compared to conventional immunotherapy, the clinical efficacy is substandard. The safety and tolerance of these new modalities should to be inspected. Additionally, developing “immunomodulatory factor-loaded NPs” may advance the efficiency of vaccines for immunotherapy.

This is an emerging area, and it is anticipated that with growth in proteomics research on the “mechanism of cancer origin, MDR, occurrence,” more NP-based drugs can be exploited. Compared to the mammoth amount of investigations, only a few NP-based drugs are actually in use, a few others in clinical trials, and most in the exploratory stage. For rational nanotechnology design, more efforts must be reserved in “understanding toxicity, cellular and physiological factors that regulate NP-based drug delivery, EPR, and PC mechanism” in the human body. Based on the evidence cited above, we presuppose that the revolution in clinical translation for NP-based cancer therapy will be attained with nanotechnology and cancer therapy development.

Authors’ Contributions

SG and SQ concepted the topic; analyzed and interpreted the data; drew figures; and wrote the draft paper. TMK reviewed, edited and corrected figures and manuscript. All authors approved the final manuscript.

The authors did not receive any external funding.

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research articles for nanoparticles

Chemical Communications

Microalgae as a potential natural source for the green synthesis of nanoparticles.

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* Corresponding authors

a Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco A.C, Unidad de Biotecnología Industrial, Camino al Arenero #1227, Col. El Bajío Arenal, 45019 Zapopan, Jalisco, Mexico E-mail: [email protected]

b Centro de Investigación en Ingeniería y Ciencias Aplicadas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa, Cuernavaca, Morelos, Mexico E-mail: [email protected]

The increasing global population is driving the development of alternative sources of food and energy, as well as better or new alternatives for health and environmental care, which represent key challenges in the field of biotechnology. Microalgae represent a very important source material to produce several high-value-added bioproducts. Due to the rapid changes in the modern world, there is a need to build new materials for use, including those in the nanometer size, although these developments may be chronological but often do not occur at a time. In the last few years, a new frontier has opened up at the interface of biotechnology and nanotechnology. This new frontier could help microalgae-based nanomaterials to possess new functions and abilities. Processes for the green synthesis of nanomaterials are being investigated, and the availability of biological resources such as microalgae is continuously being examined. The present review provides a concise overview of the recent advances in the synthesis, characterization, and applications of nanoparticles formed using a wide range of microalgae-based biosynthesis processes. Highlighting their innovative and sustainable potential in current research, our study contributes towards the in-depth understanding and provides latest updates on the alternatives offered by microalgae in the synthesis of nanomaterials.

Graphical abstract: Microalgae as a potential natural source for the green synthesis of nanoparticles

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research articles for nanoparticles

A. A. Arteaga-Castrejón, V. Agarwal and S. Khandual, Chem. Commun. , 2024, Advance Article , DOI: 10.1039/D3CC05767D

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Drivers of Anthropogenic Nanoparticle Emissions - Characteristics, Adverse Effects and Control Strategy and Management

Statistical optimization for greener synthesis of multiefficient silver nanoparticles from Hypocrea lixii GGRK4 culture filtrate and their eco-friendly applications Provisionally Accepted

  • 1 Maharshi Dayanand University, India

The final, formatted version of the article will be published soon.

The culture filtrate of Hypocrea lixii GGRK4 played a vital role as a reducing and stabilizing agent in the myco-synthesis of AgNPs using silver nitrate (AgNO3). The extracellular extract derived from fungi emerged as a noteworthy option for synthesizing silver nanoparticles (AgNPs) due to its potential composition of metabolites, including enzymes and other bioactive substances. Hence, the presence of a dark brown colour serves as a key indicator for the biosynthesis of AgNPs through the reduction of Ag (I) ions to Ag by the fungal culture filtrate. To facilitate the synthesis of AgNPs, a combination of hybrid technologies, specifically the "one factor at a time" approach and statistical tools such as Response Surface Methodology, was employed using a face-cantered central composite design (FCCCD). Utilizing a modified CX medium with a pH of 5.02 supported the fungi synthesising AgNPs at a temperature of 30℃. The multiefficient AgNPs were characterized through various techniques, including UV-visible Spectrophotometry, zeta size and potential analysis using a Zeta size analyser, Transmission Electron Microscopy (TEM), X-ray Diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and fluorescence spectroscopy. The biosynthesized AgNPs have significant associated functional groups revealed by FTIR analysis. TEM histogram analysis shows these multiefficient AgNPs have a size of 17.34 nm. Similarly, it has 450 nm and 390 nm of emission and excitation spectra, revealed by fluorescence spectra analysis. Compared to standard, the biosynthesized AgNPs have significant antibacterial, free radical scavenging properties and dye degradation capability. Additionally, the half-maximal inhibitory concentration (IC50) value was found statistically significant based on t-test analysis. Finally, the biosynthesized AgNPs could be used in potential applications encompassing eco-friendly degradation, antimicrobial activity, and therapeutic applications such as free radical scavenging properties.

Keywords: silver nanoparticles, Extracellular biosynthesis, Antimicrobial efficacy, Antioxidant property, Response Surface Methodology

Received: 09 Feb 2024; Accepted: 27 Mar 2024.

Copyright: © 2024 Gupta, Koli and Kapoor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Guddu K. Gupta, Maharshi Dayanand University, Rohtak, India Dr. Rajeev K. Kapoor, Maharshi Dayanand University, Rohtak, India

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Insects have been shown to have the ability to detect different chemical agents. Here, the authors present a nanomaterial-assisted neuromodulation strategy to augment the chemosensory abilities of insects via photothermal effect and on-demand neurotransmitter release from cargo-loaded nanovehicles to augment natural sensory function.

  • Prashant Gupta
  • , Rishabh Chandak
  •  &  Srikanth Singamaneni

Article 19 January 2024 | Open Access

In vivo real-time positron emission particle tracking (PEPT) and single particle PET

In vivo positron emission particle tracking (PEPT) remains a challenge due to the lack of single-particle tracers. Here a sub-micrometre silica particle has been radiolabelled and isolated with high specific activity, allowing the dynamic tracing of a single particle in vivo using PEPT in mice.

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  • , Laurence Vass
  •  &  Rafael T. M. de Rosales

Article | 16 January 2024

Controlled adsorption of multiple bioactive proteins enables targeted mast cell nanotherapy

Proteins absorbed on nanomaterials often lose function due to denaturation. A poly(propylene sulfone) nanoparticle with site-specific dipole relaxation has been reported, which allows proteins to anchor to the nanoparticle without disrupting the hydrogen bonding or structure maintaining the protein functionality.

  • , Clayton H. Rische
  •  &  Evan A. Scott

Article 15 January 2024 | Open Access

Urease-powered nanobots for radionuclide bladder cancer therapy

Bladder cancer treatment suffers from low therapeutic efficacy. Here the authors present radioactive 131 I-labelled urease-powered nanobots that exhibit enhanced accumulation at the tumour site, enabling effective radionuclide therapy at low doses as an alternative treatment option for bladder cancer.

  • Cristina Simó
  • , Meritxell Serra-Casablancas
  •  &  Samuel Sánchez

Article | 12 January 2024

Nanoreceptors promote mutant p53 protein degradation by mimicking selective autophagy receptors

Protein degradation is a powerful tool for a range of applications and therapies. Here, a selective autophagy receptor mimetic against mutant p53 protein is developed to substantially elevate autophagy levels and to recognize and transport mutant proteins for autophagy-mediated degradation and anticancer effect.

  • Xiaowan Huang
  • , Ziyang Cao
  •  &  Yunjiao Zhang

Article | 11 January 2024

Inhalable extracellular vesicle delivery of IL-12 mRNA to treat lung cancer and promote systemic immunity

Cytokine interleukin-12 (IL-12) has potential for tumour suppression yet off-target effects limit potential applications. Here the authors report on the delivery of IL-12 mRNA encapsulated in extracellular vesicles to lungs via inhalation and demonstrate the immunotherapeutic potential of targeted cytokine mRNA therapy.

  • Mengrui Liu
  •  &  Ke Cheng

News & Views | 02 January 2024

Oral insulin with reduced hypoglycaemic episodes

Chitosan/glucose co-polymers encapsulating silver sulfide quantum dots can be used to improve oral delivery of insulin in different animal models without hypoglycaemic incidents.

  • Mulham Alfatama

Article 02 January 2024 | Open Access

Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia

Insulin injections are not ideal and have an increased risk of hypoglycaemia. A preferable oral formulation based on silver sulfide quantum dots coated with a chitosan/glucose polymer is discussed, which has controlled insulin release and reduced risk of hypoglycaemia, and demonstrates applications in rodent and non-human primate models.

  • Nicholas J. Hunt
  • , Glen P. Lockwood
  •  &  Victoria C. Cogger

News & Views | 29 December 2023

Intracerebral fate of engineered nanoparticles

Organic and inorganic nanoparticles have different clearance mechanisms from the brain resulting in different biological fates and retention times.

  • Elizabeth Nance

Article | 29 December 2023

Intracerebral fate of organic and inorganic nanoparticles is dependent on microglial extracellular vesicle function

Nanoparticle clearance is critical for safety and therapeutic applicability. Here the authors report the modulatory role of microglial extracellular vesicles on the brain clearance of organic and inorganic nanoparticles and provide a strategy to control their intracerebral fate.

  • Jinchao Gao
  • , Qingxiang Song
  •  &  Xiaoling Gao

Review Article | 27 December 2023

Strategies for non-viral vectors targeting organs beyond the liver

Nanoparticles naturally accumulate in the liver; this can be a major limitation to any therapy needing delivery to other organs or tissues. Here the authors review the reason for predominant liver uptake and explore different strategies used to target non-viral gene delivery nanoparticles to other organs and tissues.

  • Jeonghwan Kim
  • , Yulia Eygeris
  •  &  Gaurav Sahay

Perspective | 18 December 2023

Entry and exit of extracellular vesicles to and from the blood circulation

This Perspective discusses the current understanding of extracellular vesicles within the context of their movement into and out of blood circulation, with an outlook on leveraging extracellular vesicle nanobiology for mechanistic insights as well as diagnostic and nanotherapeutic applications in both physiological and pathological contexts.

  • Dalila Iannotta
  •  &  Joy Wolfram

Article | 20 November 2023

Combinatorial development of nebulized mRNA delivery formulations for the lungs

Nebulized mRNA delivery has broad therapeutic potential but has proven challenging. Here, the authors report on a modified lipid nanoparticle with improved conditions to allow nebulization and demonstrate its application for delivering mRNA to the lungs.

  • Allen Y. Jiang
  • , Jacob Witten
  •  &  Daniel G. Anderson

Article | 09 November 2023

Microplastic fragmentation by rotifers in aquatic ecosystems contributes to global nanoplastic pollution

Here the authors show that the trophi or jaws of the chitinous masticatory apparatus of marine and freshwater zooplankton rotifers can grind microplastics, independent of polymer composition, and generate particulate nanoplastics, which may accelerate the nanoplastic flux in global surface waters.

  •  &  Baoshan Xing

Article | 30 October 2023

A modular approach to enhancing cell membrane-coated nanoparticle functionality using genetic engineering

Synthetic nanoparticles coated with cell membranes show immune evasion and circulate longer. Here, a genetically engineered cell membrane expressing a SpyCatcher anchor is used as a modular nanotherapeutic drug delivery platform for high-affinity targeting and suppression of ovarian cancer.

  • Nishta Krishnan
  • , Yao Jiang
  •  &  Liangfang Zhang

News & Views | 26 October 2023

Biohybrid nanoparticles for treating arthritis

A biohybrid nanoparticle formulation effectively treats rheumatoid arthritis by concurrently providing symptom relief and restoring proper immune function.

  • Ronnie H. Fang

Article | 26 October 2023

Ceria-vesicle nanohybrid therapeutic for modulation of innate and adaptive immunity in a collagen-induced arthritis model

Rheumatoid arthritis involves both inflammation and immune dysfunction, yet most therapies only target one aspect. Here, the authors report on ceria nanoparticle vesicle hybrids producing anti-inflammatory action and immunomodulation to relieve symptoms and restore normal function.

  • , Hee Su Sohn
  •  &  Taeghwan Hyeon

Article | 21 September 2023

Exploring the host range for genetic transfer of magnetic organelle biosynthesis

Biosynthesis of magnetosomes is of interest for a range of applications. Here, factors needed for magnetosome biosynthesis are evaluated and new diverse bacteria are engineered to biofabricate magnetic nanoparticles, facilitating translation to biotechnology and nanomedicine.

  • Marina V. Dziuba
  • , Frank-Dietrich Müller
  •  &  Dirk Schüler

Article | 18 September 2023

Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics

Here, the authors find a decrease in hepatic phagocytic uptake of nanoparticles in old mice due to age-associated downregulation of the scavenger receptor MARCO, which led to improved tumour delivery and antitumour efficacy of cancer nanomedicine, showing the need to consider age as a factor in therapeutics.

  • , Weiye Deng
  •  &  Wen Jiang

Article | 14 September 2023

Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours

Nanoparticle penetration into tumours is an obstacle to cancer therapeutics. Here the authors show that the tumour vascular basement membrane constitutes a barrier that reduces nanoparticle delivery and demonstrate an immune-driven strategy to overcome the barrier, increasing nanoparticle movement into tumours.

  • , Qirui Liang
  •  &  Yucai Wang

Article 14 September 2023 | Open Access

Wireless electrical–molecular quantum signalling for cancer cell apoptosis

Quantum biological electron transfer has potential in diagnostic and therapeutic settings. Here the authors report the triggered apoptosis of cancer cells using electricical input to wirelessly induce redox interactions at bio-nanoantennae in proximity to cancer cells.

  • , Jonathan Gosling
  •  &  Frankie J. Rawson

Article 17 August 2023 | Open Access

Programmable multispecific DNA-origami-based T-cell engagers

A synthetic nanocarrier based on DNA origami chassis offers control over valency, orientation and spatial arrangement of antibodies for simultaneously engaging immune signalling pathways, checkpoint inhibition and targeted co-stimulation in anticancer immunotherapy in vivo.

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  •  &  Hendrik Dietz

Article | 03 August 2023

Electroactive membrane fusion-liposome for increased electron transfer to enhance radiodynamic therapy

Here the authors report on exoelectrogenic bacteria-derived membrane fusion-liposome-coated titanium dioxide nanoparticles to mimic extracellular electron transfer to enhance superoxide anion production under low-dose X-ray irradiation for radiodynamic therapy.

  • Ying-Chi Chen
  • , Yi-Ting Li
  •  &  Chen-Sheng Yeh

Article | 27 July 2023

Precise electrokinetic position and three-dimensional orientation control of a nanowire bioprobe in solution

A versatile electrokinetic trap overcomes rotational and translational Brownian motion for simultaneously controlling the two-dimensional position with a precision of up to 20 nm and 0.5° in the three-dimensional angle of an untethered nanowire under an optical microscope.

  • , Daniel Teal
  •  &  Donglei Emma Fan

Close the cancer–immunity cycle by integrating lipid nanoparticle–mRNA formulations and dendritic cell therapy

Overcoming the immunosuppressive tumour microenvironment is a challenge. A strategy to close the cancer–immunity cycle has been reported by integrating lipid nanoparticle–mRNA formulations and dendritic cell therapy to promote tumour elimination and develop antitumour immunity.

  • Yuebao Zhang
  • , Xucheng Hou
  •  &  Yizhou Dong

Universal, label-free, single-molecule visualization of DNA origami nanodevices across biological samples using origamiFISH

Signal amplification through hybridization chain reaction by targeting conserved regions of the M13mp18 bacteriophage-based scaffold sequences is used for in situ imaging of unlabelled DNA origami nanostructures.

  • Wendy Xueyi Wang
  • , Travis R. Douglas
  •  &  Leo Y. T. Chou

Article 17 July 2023 | Open Access

DNA-origami-directed virus capsid polymorphism

DNA and RNA origami nanostructures direct the size, shape and topology of different virus capsids in a user-defined manner while shielding encapsulated origamis from degradation.

  • , Sharon Saarinen
  •  &  Mauri A. Kostiainen

Article | 10 July 2023

Transport by circulating myeloid cells drives liposomal accumulation in inflamed synovium

PEGylated liposomal accumulation in inflamed regions has mainly been attributed to the enhanced permeation and retention effect. An arthritis model that chemotactically attracted myeloid cells shows that monocytes and neutrophils play an essential role in liposome delivery towards inflamed joints.

  • Joke Deprez
  • , Rein Verbeke
  •  &  Ine Lentacker

Article | 26 June 2023

Efficient solvent- and hydrogen-free upcycling of high-density polyethylene into separable cyclic hydrocarbons

Ru nanoparticles on HZSM-5 catalysed solvent- and hydrogen-free upcycling of high-density polyethylene into a separable distribution of linear (C 1 to C 6 ) and cyclic (C 7 to C 15 ) hydrocarbons.

  •  &  Jie Zeng

Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines

A lipid nanoparticle (LNP) component—an adjuvant lipidoid—is developed to enhance the adjuvanticity of LNPs, which significantly increases the innate and adaptive responses of the COVID-19 mRNA vaccines with good tolerability in mice.

  • Xuexiang Han
  • , Mohamad-Gabriel Alameh
  •  &  Michael J. Mitchell

Article | 22 June 2023

Fluorescence-amplified nanocrystals in the second near-infrared window for in vivo real-time dynamic multiplexed imaging

Lanthanide downshifting nanoparticles with tunable emissions in the NIR-IIb sub-window (1,500–1,700 nm) region are ideal for deep-tissue imaging. Biofunctionalized core–shell, cubic-phase thulium-based nanoprobes show the non-invasive imaging of murine cerebral vasculature and the tracking of single immune cells and their extravasation in an inflammatory microenvironment.

  • , Ying Chen
  •  &  Fan Zhang

Analysis 08 May 2023 | Open Access

An ancestral molecular response to nanomaterial particulates

While engineered nanomaterials are relatively new, organisms have been exposed to natural nanoparticles over vast periods of time. Here the authors explore the possibility that common mechanisms of response to nanomaterials may have resulted from a long evolutionary exposure history to natural nano-sized matter.

  • G. del Giudice
  •  &  D. Greco

Article 04 May 2023 | Open Access

DNA storage in thermoresponsive microcapsules for repeated random multiplexed data access

Microcompartments with a temperature-responsive membrane are used to stably localize DNA-encoded files, which enables parallel, repeated polymerase-chain-reaction-based random access and DNA file sorting using fluorescent barcodes.

  • Bas W. A. Bögels
  • , Bichlien H. Nguyen
  •  &  Tom F. A. de Greef

Research Briefing | 02 May 2023

A floatable photocatalytic nanocomposite to facilitate scale-up of solar hydrogen production

A floatable photocatalytic platform made from a porous elastomer–hydrogel nanocomposite has been developed for converting solar energy into hydrogen fuel. This platform enables efficient light delivery, a facile supply of reactant and rapid product separation to achieve high hydrogen-evolution rates. Large-scale and seawater experiments indicate the potential for scale-up and practical application.

Article | 27 April 2023

Tailoring renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery

Optimizing the retention of drug delivery nanocarriers for improved cancer therapy has the potential to improve clinical outcomes. Here the authors screen 20 renal-clearable zwitterionic cyclodextrin-based nanocarriers for optimized biodistribution and tumour retention, demonstrating application in colorectal cancer models.

  • Min-Jun Baek
  • , Duy-Thuc Nguyen
  •  &  Dae-Duk Kim

Floatable photocatalytic hydrogel nanocomposites for large-scale solar hydrogen production

Floatable hydrogel nanocomposites, with facile intercalation of various photocatalysts, effectively produce hydrogen. The easily scalable nature of the nanocomposites demonstrates the practical application of this new type of photocatalytic platform.

  • Wang Hee Lee
  • , Chan Woo Lee

News & Views | 20 April 2023

Artificial intelligence assists nanoparticles to enter solid tumours

Single blood vessel analysis by artificial intelligence (AI) reveals heterogeneous vascular permeability among different tumour types, which is leveraged in rationally designing protein nanoparticle-based drug delivery systems to achieve active trans-endothelial permeability in tumours.

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research articles for nanoparticles

ScienceDaily

Accelerating CAR T cell therapy: Lipid nanoparticles speed up manufacturing

Penn Engineers have developed a novel method for manufacturing CAR T cells, one that takes just 24 hours and requires only one step, thanks to the use of lipid nanoparticles (LNPs), the potent delivery vehicles that played a critical role in the Moderna and Pfizer-BioNTech COVID-19 vaccines.

For patients with certain types of cancer, CAR T cell therapy has been nothing short of life changing. Developed in part by Carl June, Richard W. Vague Professor at Penn Medicine, and approved by the Food and Drug Administration (FDA) in 2017, CAR T cell therapy mobilizes patients' own immune systems to fight lymphoma and leukemia, among other cancers.

However, the process for manufacturing CAR T cells themselves is time-consuming and costly, requiring multiple steps across days. The state of the art involves extracting patients' T cells, then activating them with tiny magnetic beads, before giving the T cells genetic instructions to make chimeric antigen receptors (CARs), the specialized receptors that help T cells eliminate cancer cells.

Now, Penn Engineers have developed a novel method for manufacturing CAR T cells, one that takes just 24 hours and requires only one step, thanks to the use of lipid nanoparticles (LNPs), the potent delivery vehicles that played a critical role in the Moderna and Pfizer-BioNTech COVID-19 vaccines.

In a new paper in Advanced Materials , Michael J. Mitchell, Associate Professor in Bioengineering, describes the creation of "activating lipid nanoparticles" (aLNPs), which can activate T cells and deliver the genetic instructions for CARs in a single step, greatly simplifying the CAR T cell manufacturing process. "We wanted to combine these two extremely promising areas of research," says Ann Metzloff, a doctoral student and NSF Graduate Research Fellow in the Mitchell lab and the paper's lead author. "How could we apply lipid nanoparticles to CAR T cell therapy?"

In some ways, T cells function like a military reserve unit: in times of health, they remain inactive, but when they detect pathogens, they mobilize, rapidly expanding their numbers before turning to face the threat. Cancer poses a unique challenge to this defense strategy. Since cancer cells are the body's own, T cells don't automatically treat cancer as dangerous, hence the need to first "activate" T cells and deliver cancer-detecting CARs in CAR T cell therapy.

Until now, the most efficient means of activating T cells has been to extract them from a patient's bloodstream and then mix those cells with magnetic beads attached to specific antibodies -- molecules that provoke an immune response. "The beads are expensive," says Metzloff. "They also need to be removed with a magnet before you can clinically administer the T cells. However, in doing so, you actually lose a lot of the T cells, too."

Made primarily of lipids, the same water-repellent molecules that constitute household cooking fats like butter and olive oil, lipid nanoparticles have proven tremendously effective at delivering delicate molecular payloads. Their capsule-like shape can enclose and protect mRNA, which provides instructions for cells to manufacture proteins. Due to the widespread use of the COVID-19 vaccines, says Metzloff, "The safety and efficacy of lipid nanoparticles has been shown in billions of people around the world."

To incorporate LNPs into the production of CAR T cells, Metzloff and Mitchell wondered if it might be possible to attach the activating antibodies used on the magnetic beads directly to the surface of the LNPs. Employing LNPs this way, they thought, might make it possible to eliminate the need for activating beads in the production process altogether. "This is novel," says Metzloff, "because we're using lipid nanoparticles not just to deliver mRNA encoding CARs, but also to initiate an advantageous activation state."

Over the course of two years, Metzloff carefully optimized the design of the aLNPs. One of the primary challenges was to find the right ratio of one antibody to another. "There were a lot of choices to make," Metzloff recalls, "since this hadn't been done before."

By attaching the antibodies directly to LNPs, the researchers were able to reduce the number of steps involved in the process of manufacturing CAR T cells from three to one, and to halve the time required, from 48 hours to just 24 hours. "This will hopefully have a transformative effect on the process for manufacturing CAR T cells," says Mitchell. "It currently takes so much time to make them, and thus they are not accessible to many patients around the world who need them."

CAR T cells manufactured using aLNPs have yet to be tested in humans, but in mouse models, CAR T cells created using the process described in the paper had a significant effect on leukemia, reducing the size of tumors, thereby demonstrating the feasibility of the technology.

Metzloff also sees additional potential for aLNPs. "I think aLNPs could be explored more broadly as a platform to deliver other cargoes to T cells," she says. "We demonstrated in this paper one specific clinical application, but lipid nanoparticles can be used to encapsulate lots of different things: proteins, different types of mRNA. The aLNPs have broad potential utility for T cell cancer therapy as a whole, beyond this one mRNA CAR T cell application that we've shown here."

This study was conducted at the University of Pennsylvania School of Engineering and Applied Science and is supported by the U.S. National Institutes of Health Director's New Innovator Award (DP2 TR002776), a U.S. National Science Foundation CAREER Award (CBET-2145491), an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET), and a Burroughs Wellcome Fund Career Award at the Scientific Interface. Further support for this paper and the researchers involved came from the Emerson Collective, U.S. National Science Foundation Graduate Research Fellowships, a U.S. National Institutes of Health Ruth L. Kirschstein National Research Service Award (F31CA260922), the National Institute of Dental and Craniofacial Research of the US National Institutes of Health (T90DE030854), the University of Pennsylvania Fontaine Fellowship, the Norman and Selma Kron Research Fellowship, and the Robert Wood Johnson Foundation Health Policy Research Scholars Program. The researchers thank the Human Immunology Core at the University of Pennsylvania (RRID: SCR_022380) for assistance with primary human T cell procurement. The HIC is supported in part by NIH P30 AI045008 and P30 CA016520.

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Materials provided by University of Pennsylvania School of Engineering and Applied Science . Original written by Ian Scheffler. Note: Content may be edited for style and length.

Journal Reference :

  • Ann E. Metzloff, Marshall S. Padilla, Ningqiang Gong, Margaret M. Billingsley, Xuexiang Han, Maria Merolle, David Mai, Christian G. Figueroa‐Espada, Ajay S. Thatte, Rebecca M. Haley, Alvin J. Mukalel, Alex G. Hamilton, Mohamad‐Gabriel Alameh, Drew Weissman, Neil C. Sheppard, Carl H. June, Michael J. Mitchell. Antigen Presenting Cell Mimetic Lipid Nanoparticles for Rapid mRNA CAR T Cell Cancer Immunotherapy . Advanced Materials , 2024; DOI: 10.1002/adma.202313226

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Nanoparticles: A New Approach to Upgrade Cancer Diagnosis and Treatment

  • Nano Review
  • Open access
  • Published: 20 May 2021
  • Volume 16 , article number  88 , ( 2021 )

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  • Zhongyang Yu 4   na1 ,
  • Lei Gao 1   na1 ,
  • Kehan Chen 2 ,
  • Wenqiang Zhang 2 ,
  • Qihang Zhang 3 ,
  • Quanwang Li 1 &
  • Kaiwen Hu 1  

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Traditional cancer therapeutics have been criticized due to various adverse effects and insufficient damage to targeted tumors. The breakthrough of nanoparticles provides a novel approach for upgrading traditional treatments and diagnosis. Actually, nanoparticles can not only solve the shortcomings of traditional cancer diagnosis and treatment, but also create brand-new perspectives and cutting-edge devices for tumor diagnosis and treatment. However, most of the research about nanoparticles stays in vivo and in vitro stage, and only few clinical researches about nanoparticles have been reported. In this review, we first summarize the current applications of nanoparticles in cancer diagnosis and treatment. After that, we propose the challenges that hinder the clinical applications of NPs and provide feasible solutions in combination with the updated literature in the last two years. At the end, we will provide our opinions on the future developments of NPs in tumor diagnosis and treatment.

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Introduction

The incidence and mortality of tumors remain high worldwide. Every year, there are nearly 14 million new cancer patients and 8 million people die of cancer-related diseases [ 1 ]. In recent years, traditional tumor treatments, such as chemotherapy, targeted therapy, radiotherapy, surgery, etc., are constantly criticized for being bogged down in progress and for many adverse reactions and unsatisfied treatment outcomes. Because of the shortcomings of traditional tumor therapies, more and more researches have begun to seek new tumor medical methods with targeting ability, effective tumor stem cell killing ability and minor adverse reactions. New tumor treatment methods include, but are not limited to, immunotherapy, targeted therapy, physical ablation, gene therapy, photodynamics therapy (PDT) and photothermal therapy (PTT) which have shown superior efficacy compared to traditional tumor therapy. The treatment methods herein all have a common feature that requires carrier cooperation. Although viruses can be used as carriers, viral vectors have been confirmed to cause insertional mutagenesis and immunogenicity [ 2 ]. Therefore, finding a safer and more effective carrier has become a top priority.

Due to nanoparticles’ small size, biosafety, drug loading, and physical properties can assist physical therapy, nanoparticles have been increasingly utilized as carriers in new tumor treatment methods. These nanoparticles-mediated therapies have virtues of multi-function, less adverse reactions and better curative effect [ 3 ]. In addition, many medical imaging technologies mediated by nanoparticles also have better clarity and accuracy, which helps accurate tumor diagnosis [ 4 ]. With the development of nanotechnology and medical technology, metals and biological materials such as gold, silver, iron, liposomes, etc. have been widely applied in the production of medical nanoparticles (NPs) [ 5 ]. At present, many researchers utilize those materials based on their physical, chemical, and/or biological properties to embed drugs, imaging agents and even genes in nanoparticles, expanding the existing field of tumor diagnosis and treatment such as drug targeted delivery, enhanced imaging, cryosurgery, PTT and PDT [ 6 ].

In addition, there is a phenomenon that most of the nanoparticles only stay in vivo and in vitro stage. However, there is a lack of literature to summarize the reasons that deter the clinical application of NPs. Therefore, this article aims to not only summarize the application status of nanoparticles in the field of tumor diagnosis and treatment, but also to find the factors that inhibit the entry of nanoparticles into clinical applications and propose feasible solutions.

Preparation and Characterization of Medical Functional Nanoparticles

Nanoparticles commonly used in medicine can be divided into three types: metal nanoparticles, non-metal nanoparticles and composite nanoparticles according to their constituent materials and functions, and their physical and chemical properties are affected by parameters such as size and shape. Therefore, in view of the functional requirements of nanoparticles in different application directions, it is very important to choose a suitable preparation process. All the preparation methods of nanoparticles can be classified into two methods: bottom up approaches and top-down approaches. The bottom-up approach is essentially through basic units (atoms, molecules and even smaller particles can be used as the basis for assembling the required nanostructures) stacked on each other to form nanoparticles, while the top-down approach is essentially a whole solid material begins to decompose into nanoparticles [ 7 ]. Table 1 lists some examples of preparing medical nanoparticles.

Among the three types of nanoparticles commonly used in medicine, metal nanoparticles are the most widely used. Metal nanoparticle materials include metals and metal oxides. The most commonly used preparation process for metal nanoparticles is the sol–gel (Sol–Gel) process proposed by Japanese scientist Sugimoto et al. in the 1990s, which is often used to prepare monodisperse metal oxide particles in liquid phase. The sol–gel method is a bottom-up preparation process. The main principle of this method for preparing metal nanoparticles is to form a uniformly dispersed sol of metal ions through chemical and physical means, and then form a gel through redox reaction. The metal nanoparticles generated in the gel can controllably nucleate, grow and deposit. As long as the monodispersity of the metal colloid used in the experiment, the concentration relationship of the metal ions and the oxidizing/reducing agent are controlled, the size of the synthesized metal nanoparticles can be controlled. Figure  1 is the schematic diagram of the sol–gel method.

figure 1

Schematic diagram of the sol–gel method

Commonly used bottom-up methods for preparing metal nanoparticles include co-precipitation, hydrothermal approach, and photochemical method. The co-deposition method is a process of nucleation, growth and aggregation in a liquid environment at the same time. When the solution is oversaturated, a large number of small-sized particles insoluble products are obtained [ 15 ]. The hydrothermal method is a process performed in a liquid environment to control the morphology of the resulting nanoparticles by controlling the vapor pressure applied to the material in the solution. In addition, there are some top-down methods for preparing metal nanoparticles, such as electrical wire explosion and ball milling. The principle of electrical wire explosion is that in the process of electric explosion, the metal atoms are evaporated and quickly cooled in the electrolyte to form oxide nanoparticles. By controlling the electrolyte composition and current intensity, finer and uniform nanoparticles can be controlled. Ball milling is a method of quickly and large-scale production of nano-particles with controllable size using machining tools such as milling planetary gears by selecting appropriate grinding time and related equipment process parameters. In addition to metal nanoparticles, this preparation method can also be applied to other types of nanoparticles.

The second common type is non-metallic nanoparticles. Non-metallic nanoparticles commonly used in medicine include polymer nanoparticles, biomolecules derived NPs, carbon-based NPs, and silica nanoparticles [ 16 , 17 , 18 ]. Among them, silica nanoparticles are the most representative. The silica surface has abundant hydroxyl groups, which facilitates the binding of probes or fluorescent groups on the surface and therefore has more flexible functionality. The commonly used synthesis methods of silica nanoparticles are the sol–gel method and the Stöber method [ 19 , 20 ]. The classic Stöber method is the simple and efficient preparation of silica nanoparticles through the hydrolysis and condensation of silicate under alkaline conditions.

With the development of nanotechnology, composite nanoparticles have been developed due to their superior functional compatibility. Metal nanoparticles have many characteristics that non-metal nanoparticles do not have, such as plasmon resonance effect (SPR), controllability in a magnetic field, etc., but metal particles are difficult to effectively degrade in the body, and excessive use has certain toxicity to cells [ 21 ]. Therefore, combining nanoparticles of different materials into composite nanoparticles through different preparation methods can achieve functional expansion. Wei et al. prepared gold nanorods (Au NRs), and then performed surface-initiated atom transfer radical polymerization (SI-ATRP) of N-isopropylacrylamide (NIPAAM) on Au NRs to synthesize near-infrared response Nano hybrids [ 22 ]. This composite nanoparticle that combines metal and polymer materials has both photothermal and near-infrared light corresponding drug release capabilities. The enveloping hydrogel shell makes this nanoparticle have better biocompatibility than single Au nanoparticles. Prakash synthesized composite NPs with Au as the core and SiO 2 as the shell through the improved Stöber method. The inert shell of the core–shell nanoparticles is beneficial to reduce the toxicity of metal particles and improve the material stability and drug-carrying capacity of the original single metal NPs [ 23 ].

In addition to the traditional preparation methods of nanoparticles mentioned above, with the development of nanotechnology science, new requirements for ecological and environmental protection have been put forward, so new environmentally-friendly nanoparticle synthesis methods have emerged [ 24 ]. For the first time, Hajar et al. used Stevia rebaudiana as a biological reducing agent to successfully synthesize ZnS nanoparticles with a particle size ranging from 1 to 40 nm. The ZnS nanoparticles synthesized in this way have good biocompatibility [ 25 ]. According to the principles of green chemistry, Miri et al. used P. farcta (A plant belonging to Leguminosae) extract to quickly synthesize CeO 2 NPs with a particle size of about 30 nm. This kind of nanoparticles has good biocompatibility [ 26 ].

Nanoparticles for Medical Imaging

Medical imaging plays an important role in the diagnosis and treatment of tumors. Many nanoparticles, like iron oxide NPs, have optical, magnetic, acoustic, and structural properties that can enhance imaging (Fig.  2 ). Some studies have shown that introducing NPs into target tissues can improve image contrast and provide better image guidance for tumor surgery and diagnosis [ 27 ]. For example, in cryosurgery, NPs can enhance the imaging quality of the tumor and ice ball edges, which helps to cover the ice balls accurately and improve the therapeutic effect [ 28 ]. In addition, most of the nanoparticles used in imaging are made of metal. According to the difference of different imaging principles, nanoparticles will also be made of different metal materials. Table 2 lists some recent examples about NPs made by different materials for medical imaging.

figure 2

Diagrammatic illustration of imaging improved of NPs

Optical coherence tomography (OCT) is a non-invasive, micron-level resolution and biomedical imaging technology. OCT is useful in real-time diagnosis and surgical guidance. However, OCT cannot detect inelastic scattered light because this light is not coherent in the incident field [ 35 ]. Recently, many researches have proved the motion state of NPs can be able to change the amplitude of OCT, which may deal with this problem. Interfering with the movement of NPs through the magnetic field can cause local changes in light scattering. Some studies have pointed out that placing magnetic NPs in a magnetic field to control its motion can change the optical scattering in the area, so the originally incoherent inelastic scattered light can be detected. This new imaging method is magnetomotive optical coherence tomography (MMOCT) [ 36 ].

MRI is one of the most effective noninvasive tumor detection technology. Nevertheless, the lack of MRI signal comparison between biological background and cancer tissue often affects the clinical tumor diagnosis [ 37 ]. MRI is a scanning imaging method that measures the magnetization of hydrogen molecules in water molecules. Each anatomical structure presents a different image since the protons of each tissue cause different changes in magnetization. The visibility of images can be improved through applying more contrast agents [ 38 , 39 ]. The tumor-related EPR effect widely utilized in the early detection of tumors produces great contrast enhancement ability to magnetic NPs [ 40 ]. Iron oxide magnetic NPs (IONPs) which are currently the most common MRI nanoprobe contrast agents have certain cell targeting [ 41 ]. For example, studies have found that IONPs could enter healthy liver Kupffer cells during the diagnosis of liver cancer by using MRI but will be excluded from cancer cells, resulting in low-signal healthy tissue and high-signal tumor tissue [ 42 ]. Based on recent studies, proper particle surface modification and appropriate tumor-specific bio-oligomer embedding of NPs can better fix NPs in tumors to achieve clearer imaging results and can even be used for early micro tumor imaging. For example, studies have found that AuNPs targeted for human transferrin can significantly enhance the imaging effect of brain tumors [ 43 ]. Gao et al. equipped with anti-epidermal growth factor receptor monoclonal antibody (mAb) on the basis of paramagnetic NPs probes to achieve imaging of small tumors [ 44 ].

Nanoparticles for Targeted Drug Delivery

Although Chemotherapeutic drugs now are the most commonly used treatment for tumors, they still have the problem of poor target enrichment in malignant tumor areas and overaccumulation in healthy tissue [ 45 ]. This may cause the inhibition of cells hat divide vigorously, such as bone marrow, hair follicles, gastrointestinal cells and lymphocytes, leading to adverse reactions such as bone marrow suppression, mucositis, hair loss, and even death [ 46 ]. Targeted drug delivery which refers to active differentiation between normal cells and cancer cells for drug delivery has better efficacy and fewer adverse reactions than the conventional treatment [ 45 ].Many studies have confirmed that NPs can target chemotherapeutic drugs to tumor cells through active or passive targeting [ 47 ]. In addition, many experiments have found that NPs also play an important role in the targeted delivery of immune drugs [ 48 ].

As shown in Fig.  3 , passive targeting often relies on some pathophysiological characteristics of tumor tissue, including abnormal blood vessels, temperature, pH and surface charge of tumor cells [ 49 ].For example, due to the enhanced permeability and retention effect (EPR) of blood vessels in the tumor tissue, NPs with a diameter of about 400 nm can be passively transferred to the tumor tissue [ 50 ]. However, there are many limitations on the passive targeting approach in terms of physicochemical properties of NPs such as diameter, surface charge, molecular weight, hydrophobicity, or hydrophilicity. Besides, the passive targeting technique underperforms in drug diffusion efficiency and shows insufficient EPR effect in tumor cells [ 51 ]. Due to the deficiencies of passive targeting, in recent years, most research about the drug delivery NPs has shifted to active targeting (ligand targeting). Table 3 highlights some recent examples about NPs used in drug delivery.

figure 3

Diagrammatic illustration of passive targeting of NPs

Active targeting (ligand targeting) NPs often carry some ligands of tumor-specific biomarkers [ 61 ]. As shown in Fig.  4 when the ligand contacts to the receptor on the tumor surface, NPs can be internalized by the tumor cells through receptor-mediated endocytosis, and the drugs can be released due to acidic pH and specific enzymes in the intracellular environment [ 62 ]. As for targeting ligands, folic acid, transferrin, epidermal growth factor receptor (EGFR) and glycoprotein are generally utilized in current research [ 62 ]. For example, Sandoval et al. obeserved significant drug enrichment and evident efficacy in the treatment of mice with breast cancer through EGFR-targeted stearyl NPs equipped with gemcitabine [ 63 ]. Pandey et al. found that folic acid-targeted gold NPs carrying berberine hydrochloride (BHC) can effectively deliver drugs to human cervical cancer cells expressing folate receptor [ 64 ].

figure 4

Diagrammatic illustration of active targeting of NPs

In recent years, compared with chemotherapy drugs, short interfering RNA (siRNA)-mediated gene silencing therapy has been regarded as a new prospect for tumor treatment [ 64 ]. Although viruses can be used as delivery vehicles for siRNA, viral vectors have been confirmed to cause insertional mutagenesis and immunogenicity [ 65 ]. By contrast, selenium NPs are reported to have great potential as siRNA carriers, because the trace element selenium itself can reduce tumor occurrence, lower drug toxicity, and regulate immune function [ 66 ]. In addition, the surface of selenium NPs can load various tumor- targeting moieties (such as folate, hyaluronic acid and RGD peptide) to enhance tumor targeting ability [ 67 ]. Xia et al. reported that selenium NPs (RGDfC-Se@siRNA) targeted by RGDfC peptide have excellent ability to target HeLa cervical cancer [ 60 ]. Meanwhile, because RGDfC can specifically combine with α v β 3 integrin which is highly expressed by a variety of tumor cells, RGDfC-Se@siRNA NPs can be reused for targeted drug delivery for a variety of tumors [ 68 ]. In terms of structure, RGDfC-SeNPs with positive charge can tightly package negatively charged siRNA through their electrostatic interaction [ 69 ]. Through animal experiments, RGDfC-Se@siRNA NPs show the ability to efficiently enter tumor cells through clathrin-associated endocytosis. In tumor cells, it can quickly release siRNA and efficiently silence related genes and promote the generation of reactive oxygen species (ROS) to inhibit tumor cells proliferate and promote tumor cells apoptosis [ 69 ]. Additionally, multiple SeNPs have demonstrated excellent biological safety and have no obvious toxic damage to liver, kidney, heart, lung, spleen and other major organs of mice [ 60 , 70 , 71 ].

At present, although there are many NPs used in targeted drug delivery, most applications still remain in the stage of cell or animal experiments, lacking potent clinical application support. In addition, many NPs are administered intratumorally, which limits the scope of NPs applicable to tumors and lacks special NPs drug delivery tools and other drug delivery methods.

Therefore, exploring a better way to administer NPs may be a direction for the future research of targeted drug delivery NPs. According to the existing academic journals, vascular interventional administration may be a feasible way. In the assumption, first locate the position of tumor-feeding blood vessel with the help of imaging, and then use a guide wire to introduce NPs directly into the tumor-feeding blood vessel and control the movement of the NPs in a small range by applying a magnetic field simultaneously. Therefore NPs can be fixed at the proper position without being influenced by blood flow in the vessel. Otherwise, NPs targeted for drug delivery only have certain limitations. Targeting NPs will affect the systemic distribution of chemotherapeutic drugs and reduce the effect of chemotherapy on free tumor cells and micrometastasis. If they are equipped with targeted drugs, the targeting effect tends to be enhanced whereas the improvement is not evident based on the existing studies.. In addition, anti-tumor drugs are unlikely to eliminate all tumor stem cells by themselves. Nevertheless, physical therapy based on the physical characteristics of NPs tends to be more effective against the tumor stem cells. Therefore, multifunctional NPs targeting drug carriers tend to be advisable in the future, such as cryosurgery, photothermal therapy (PTT) and photodynamics therapy (PDT) etc., to form multi-functional NPs for tumor treatment.

Nanoparticles for Cryosurgery

Cryosurgery, the technique of destroying tumor tissue by freezing, has the advantages of low invasiveness, low cost, less intraoperative bleeding and less postoperative complications, but there are still disadvantages such as insufficient freezing efficiency and freezing damage to surrounding tissues [ 28 ]. Although protective agents such as antifreeze protein (AFP-1) have been utilized to assist cold ablation, the effect is still not ideal [ 72 ]. With the development of nanotechnology, the concept of nano-cryosurgery was proposed. The basic mechanism of nano-cryosurgery is to introduce NPs with specific physical or chemical properties into tumor tissues. By utilizing the properties of NPs, not only can the efficiency and effectiveness of freezing be improved, but the range adjustment and the direction of ice ball formation can be also controlled. Thus, the nano-cryosurgery is capable of killing tumor tissue and preventing surrounding healthy tissue from being frozen simultaneously [ 73 ]. The advantages of nano-cryosurgery have shown in Fig.  5 .

figure 5

Diagrammatic illustration of NPs for cryosurgery. a NPs protect health cells during cryosurgery. b NPs enhance the freezing damage and control the freezing coverage. c With the help of NPs, more ice has been formed

In cryosurgery, intracellular ice formation is the key to tumor cell damage. Meanwhile, research proves that NPs can effectively induce intracellular ice formation [ 28 ]. NPs as external particles can induce heterogeneous nucleation. Studies have found that tissues enriched with NPs freeze faster than conventional tissues and are more prone to heterogeneous nucleation. Under the same freezing conditions, ice formation of tissue with NPs is easier, indicating that NPs can significantly increase the speed and probability of ice formation in cells, which can kill tumor cells more effectively [ 74 ]. In addition, NPs with metal oxide will significantly improve the thermal conductivity in tumor tissue. For example, Liu and Deng compared the temperature response curve of pork tissues with and without NPs. They found that the tissues containing NPs cooled rapidly, and the lowest temperature could reach 115 ℃, which was much lower than that of the control group without NPs.

Since tumors are usually irregular in shape, the ice crystals produced by traditional cryosurgery tend not to cover all tumor tissue. Compared with traditional cryosurgery, the nano-cryosurgery can deal with the problem easily. Because NPs can permeate into the intracellular fluid and have good physical properties like thermal conductivity, it is possible to control the growth direction and direction of the ice ball by the distribution of NPs [ 73 ].

In cryosurgery, insufficient freezing may not completely destroy tumor tissue, and excessive freezing may damage adjacent healthy tissue. Especially when the tumor is in close contact with fragile organs, its location is deep, or its shape is irregular, the damage to the healthy tissue can be particularly serious. In recent years, phase change materials (PCMs) made from NPs have demonstrated excellent protective potential for surrounding healthy tissues during cryosurgery [ 75 ]. For example, Lv et al. microencapsulated phase change NPs with large latent heat and low thermal conductivity through liposomes, and before cryosurgery, injected microencapsulated phase change NPs into healthy tissues around the tumor and found that avoided low temperature damage to healthy tissue [ 76 ].

Although NPs have been widely used in cryosurgery, there are still a series of deficiencies. First, it is still unable to control NPs in vitro, which results in uneven distribution of NPs in tumor tissue and unsatisfactory expected function. Secondly, although there are a variety of magnetic nanoparticles, the actual effect of in vitro magnetic field control NPs is still not ideal. In addition, the nano-cryosurgery is lack of clinical experimental research, and many NPs are still in the laboratory stage.

The application of NPs in cold ablation can be generally divided into two types: synergistic effect and protective effect, which are different in terms of the design requirements of NPs and the distribution in vivo. In the future, nano-cryosurgery may be assisted by a variety of NPs, viz, synergistic NPs are distributed inside the tumor while protective NPs are distributed around the tumor. In addition, many nano-positioning devices, such as puncture-designed 3D printed coplanar template (3DPCT) which currently used for tumor positioning before radioactive particle implantation may be used in cryosurgery. Prior to the cryosurgery, protective NPs can be punctured and injected around tumor to protect the surrounding healthy tissue by 3D printing coplanar template (3DPCT) and CT guidance. The NPs are able to assist the cryosurgery ice balls to cover the irregular edge of tumor. Then synergistic NPs will be introduced into the tumor tissue through the preset ablation site puncture or vascular intervention to perform cold ablation. This nano-cryosurgery technique can not only overcome the difficulties of cold ablation of irregular tumors but also increase the effect of cold ablation and reduce the damage to healthy tissue. This method may become the future research direction of nano-cryosurgery. Table 4 highlights some recent examples about NPs used in cryosurgery.

Nanoparticles for PTT and PDT

At present, photothermal therapy (PTT) and photodynamic therapy (PDT) based on nanoparticles (NPs) have shown the virtues of strong efficacy, small invasion and mild adverse effects during tumor treatment (Fig.  6 ) [ 80 ]. In addition to killing tumor cells directly, fragments of dead tumor cells produced by PDT and PTT treatment can be used as potential antigens to trigger a continuous immune response, called photothermal and photodynamic immunotherapy [ 81 ]. Nanoparticles designed based on the PTT treatment concept are a new type of light-to-heat conversion nanomaterials, which can convert light energy into heat energy to kill cancer cells. Compared with traditional photothermal conversion materials, nanoparticles have many advantages. First, NPs can achieve the effect of tumor targeted aggregation through particle surface modification, which contributes to higher enrichment ability of target tumor [ 82 , 83 ]. Second, nanoparticles have better imaging capabilities than traditional photothermal materials, which can be accurately positioned by CT, MRI and photoacoustic imaging [ 84 , 85 ]. Targeted nanoparticles synthesized by Pan et al. can perform PTT under 0.2 W/cm 2 NIR to induce tumor cell apoptosis by destroying the tumor cell nuclear DNA and inhibiting the DNA repair process [ 86 ]. Table 5 lists some recent examples about NPs used in PDT and PTT.

figure 6

Diagrammatic illustration of NPs-mediated PDT and PTT. a NPs promote the generation of reactive oxygen. b NPs enhance tumor damage during PTT

In addition, some studies have found that nanoparticle-mediated PTT can reverse tumor multidrug resistance (MDR). The overexpression of drug transporters, multidrug resistance-associated protein 1 (MRP1), and p-glycoprotein (p-gp) are generally believed to cause MDR in various tumors [ 95 ]. For example, multifunctional light-triggered nanoparticles designed by Li et al. can inhibit the expression of MRP1 in PTT, which consequently reverses the drug resistance of A549R cells [ 96 ]. Wang et al. reported that both gold nanoparticles and carbon-based nanoparticles can overcome DOX resistance by promoting the expression of heat shock factor trimer in PTT, thereby inhibiting the generation of p-gp [ 97 , 98 ]. Besides, nanoparticle-mediated PTT can also increase the effectiveness of chemotherapy by destroying the integrity of tumor cell membranes [ 99 ].

PDT is a treatment that uses the selective retention of photosensitizing substances (PSs) in tumor tissue under the activation of specific wavelength excitation light and the presence of molecular oxygen to produce singlet oxygen and other reactive oxygen species, which leads to tumor cell apoptosis and necrosis [ 100 ]. However, traditional PS has poor tumor targeting, poor solubility, and instability, which is vulnerable to the internal environment [ 100 ]. Nanoparticle carriers modified by targeted molecules can not only improve the stability and biocompatibility of PS but also deliver PS to target cells, which improves the efficacy and reduces adverse effects [ 100 ]. Additionally, some common nanomaterials, like gold nanorods, have excellent PTT effects themselves. For example, Vankayala et al. found that the exposure of gold nanorods to near infra-red light (915 nm) were able to efficiently induce the generation of singlet oxygen [ 100 ].

In recent years, the role of up-conversion (UC) nanoparticles in PDT has attracted much attention. The NPs can convert long-wavelength light excitation into multiple short wavelengths, which enables the UC to replace the traditional ps-dependent short-wavelength excitation light with the near-infrared light with strong tissue penetration ability [ 101 ]. For example, Li et al. developed dual-band luminescent lanthanide nanoparticles as a PS carrier. This UC nanoparticles rely on the excitation light wavelength of 808 nm to achieve image-guided PDT without affecting imaging signals [ 102 ].

Since most photosensitive materials utilized in the phototherapy are metals, the biocompatibility of NPs designed for inorganic nanomaterials like metal ions still needs to be improved.

NPs-mediated phototherapy is now credited for not only the effectiveness against tumor but also the potential for spare internal space of nanoparticles since the therapy only utilizes the physical properties of NPs skeleton. Therefore, NPs are often multifunctioned by PDT and PTT. In the future, such NPs may be designed as dedicated NPs for tumor stem cells that are not sensitive to chemotherapy. Tumor stem cells are dormant for a long time and have a variety of drug-resistant molecules, so it is difficult to kill them by conventional treatments like chemotherapy, whereas the light therapy is more effective by killing the tumor stem cells physically. In the future, nanophysical therapy may be used with many other techniques, such as the multifunctional NPs for photothermal therapy after cryosurgery. Multifunctional NPs mediated therapy can give full play to its characteristics of low side effects, strong local lethality, and tumor stem cell killing. In addition, because nano-physiotherapy has a local killing effect and can effectively kill tumor stem cells, it may become a treatment method for small metastases.

Nanoparticles for Radiotherapy

Radiotherapy (RT) is a tumor treatment technique that kills local cells by ionizing radiation generated by rays and is currently an effective treatment for many primary and metastatic solid tumors [ 103 ]. Experiments prove that radiotherapy can effectively kill tumor stem cells [ 104 ].However, how to further improve the efficacy of radiotherapy is still a serious challenge. In recent years, nanoparticles in the field of radiotherapy have demonstrated strong radiosensitization capabilities, tumor-targeted delivery capabilities of radiosensitizing drugs, and imaging guidance enhancement capabilities [ 105 ]. At present, the most popular nanoparticles are made by high Z (atomic number) metal materials, which are featured by chemical inertness and strong radiation absorption capacity. They produce various reactions such as photoelectric effect and Compton effect after absorbing radiation, thereby releasing a variety of particles such as optoelectronics, Compton electrons, and Auger electrons. These electrons react with organic molecules or water in tumor cells to generate a large number of free radicals, leading to synergistic chemotherapy [ 106 ]. Common chemotherapy-sensitized NPs are currentlycategorized as precious metals, iron oxides, and semiconductors in terms of materials.

Precious metals NPs are made of high atomic number metal materials such as gold, silver, gadolinium, hafnium, platinum, bismuth, etc. [ 107 ]. Among them, gold nanoparticles have become the most popular NPs due to their good biocompatibility, chemical stability, and relatively strong photoelectric absorption coefficient [ 108 ]. In 2000, Herold et al. discovered the chemosensitizing ability of gold nanoparticles in kilovoltage X-rays. Nowadays, the specific mechanism of chemosensitization of gold nanoparticles is not yet clear, and the mainstream view believes that it depends on the photoelectric absorption capacity of high atomic number [ 109 ]. In addition to this, there are studies suggesting that the presence of gold nanoparticles improve the chemical sensitization of DNA to radiation, which increases the DNA damage induced by ionizing radiation (IR). At the same time, gold NPs can catalyze the mechanism of radiotherapy sensitization such as free radical production [ 105 ]. For instance, Liu found that AuNPs could significantly increase the production of hydroxyl radicals as well as the killing effect of x-rays and fast carbon ions on cells [ 110 ]. The hypothesis of the chemotherapy sensitization mechanism of other precious metals is similar to that of gold nanoparticles. Particularly, platinum NPs have an anti-tumor effect due to the inherent nature. Consequently, platinum NPs are expected to play the role of chemotherapy and radiotherapy simultaneously. However, the number of relevant research reports is insufficient, and the sensitizing effect of platinum NPs is also questionable. For example, Charest et al. reported that liposomal formulation of cisplatin was able to increase the uptake of platinum by tumor cells, and could enhance the killing of F98 glioma cells by γ-rays at the same time [ 111 ]. On the contrary, Jawaid et al. reported that platinum NPs would reduce the generation of reactive oxygen species (ROS) and the efficacy of radiotherapy during chemotherapy [ 112 ].

Iron oxide nanoparticles (IONs), especially the superparamagnetic magnet Fe 3 O 4 , have shown great potential in image-guided tumor radiotherapy because they are capable of enhancing the dose of radiotherapy and MRI imaging, whereas its sensitization mechanism is not clear yet. Its sensitization mechanism is not yet clear. Some studies believe that iron oxide NPs mainly catalyze the generation of ROS through Fenton's reaction and Haber–Weiss reaction. Then the highly reactive ROS will kill tumors [ 112 , 113 , 115 ]. Other studies propose that the mechanism depends on the radiation sensitization and synergistic effects of magnetic nanoparticles. As Khoei reported, iron oxide NPs can improve the radiosensitization of prostate cancer cells in vitro [ 116 ]. Huang et al. pointed out that cross-linked dextran-coated IONs (CLIONs) could be internalized by HeLa cells and EMT-6 mouse breast cancer cells, which enhances radiation therapy [ 117 ]. Although the synergistic effect of iron oxide NPs is obvious, its biological safety still needs to be improved. Many studies have proved that the biocompatibility and chemical stability of iron oxide NPs are questionable, and it has certain toxicity [ 118 ].

Semiconductor NPs like silica NPs have also been found to have a synergistic effect on radiotherapy. For instance, Zhang et al. used flow cytometry analysis and MTT experiments to find that mesoporous silica NPs can effectively enhance the radiotherapy of glioblastoma [ 119 ]. He et al. reported the mechanism of radioactive enhancement of silica NPs. He found that under X-ray irradiation, silica nanoparticles could produce fine hydroxyl radicals, which can effectively kill tumor cells [ 120 ].

At present, although many experiments have confirmed that NPs were able to sensitize radiotherapy, the specific mechanism of sensitization is still unclear, which hinders the development of new sensitized NPs. There are some doctrines like sensitizing chemotherapy that promotes free radical production. Nevertheless, there is a lack of a quantitative relationship among the amount of free radical production, radiation intensity, and physical data of nanoparticles. In addition, most sensitized NPs are made of high atomic number metals. These metals have many disadvantages in human body such as difficulty in self-metabolism and biodegrading. Meanwhile, long-term accumulation of the metals will produce toxicity, which limits the safe use of radiosensitized NPs. Moreover, compared with the radiotherapy sensitization NPs, fewer studies focused on NPs which can prevent the adverse reactions of radiotherapy and protect healthy tissues. The research on radiotherapy protective NPs is short in quantities.

In the future, searching for NPs material that can be metabolized by the kidney, biometabolized, biocompatible, stable in physicochemical properties, and inherently less toxic, or looking for surface modification that can help the body metabolize NPs may become a research direction for sensitized NPs. Moreover, although there have been many NPs studies on multi-function, namely simultaneous sensitization of radiotherapy and chemotherapy, there are still many potentials in this field, which are worthy of focus in the future. The development of protective NPs that can protect normal tissues around radiotherapy and alleviate poor defense against radiotherapy may also become a research direction.

The poor curative effect, inefficient targeting ability, various side effects, and potential biological risk are some of the unfavorable attributes of conventional cancer therapy and diagnosis. In recent years, advanced nanotechnology and molecular cell biology have promoted the applications of NPs in cancer field. Not only metal NPs, but also many lipid, nucleic acid and silicon NPs showed evident outperformance in cancer diagnosis and treatment.. Moreover, new generation of NPs is no longer limited to solo but multiple functions. For example, gold-coated poly(lactic-co-glycolic acid) (PLGA) NPs equipped with PD-1 blockers which were designed by Luo et al. can not only target drug delivery but also mediate PTT therapy [ 121 ]. (Pd @ Au) / Fe3O4 Spirulina NPs with doxorubicin created by Wang et al. demonstrated the functions of photothermal therapy, delivery of chemotherapy drugs, and magnetic field control in cell experiments [ 122 ]. Multifunctional nanoparticles will become the trend of future research.

At present, we find that most of the nanoparticles only stay in vivo and in vitro stage. According to this review, we think the following reasons hinder the clinical application of NPs.

Lack of injection routes and methods

Most NPs are injected into body via puncture or intravenous injection. Therefore, the blood flow will take away NPs, making NPs difficult to stay in the target area for a long time, which leads to just few NPs that can be uptaked by tumor cells. Low-concentration drugs cannot produce the expected therapeutic effect, and low-concentration NPs also affect the physical killing effects of PDT, PTT, cryosurgery, and radiotherapy. In our opinion, magnetic NPs platform may be a solution. There have been many in vitro and in vivo experiments that have proved the feasibility of using the three-dimensional magnetic field to control the movement of NPs against blood flow [ 122 , 123 , 125 ]. However, how to solve the interference of the human body to the magnetic field, how to solve the impact of blood cells colliding with NPs, and how to control a large number of NPs in a group are still in discovery.

Difficulty in localization of NPs in vivo

Compared with the human body, the size of NPs is too tiny. Even if NPs are loaded with fluorescent proteins, it is still difficult for conventional imaging equipment (CT, X-ray, MRI) to locate the NPs in the human body in real time. To deal with this challenge, photoacoustic computed tomography (PACT) may be a solution. Photoacoustic computed tomography (PACT) has attained high spatiotemporal resolution (125-μm in-plane resolution and 50-μs frame −1 data acquisition), deep penetration (48-mm tissue penetration in vivo), and anatomical and molecular contrasts [ 126 ]. Because of excellent performance, PACT has great potential in NPs localization imaging in vivo. The PACT-guided microrobotic system designed by Wu et al. has achieved controlled propulsion and prolonged cargo retention in vivo of NPs with a diameter of 50 μm [ 127 ]. Although the current resolution and deep penetration of PACT are still insufficient, it is superior to conventional imaging equipment (CT, X-ray, MRI) in terms of NPs imaging positioning.

Difficulty of degrading in the human body

Although NPs are made of high biosafety materials, there is still a risk of damages to liver, kidney, and other organs if they stay in the body for a long time and cannot be degraded or excreted The use of materials that will be disintegrated after near-infrared light irradiation to fabricate NPs may be a solution to this problem. Recently, more and more NPs have been produced by these materials. Such NPs mediate PTT while loading drugs, meanwhile, the substances produced by the disintegration of NPs can be rapidly metabolized by the human body. In addition, the use of more biocompatible and degradable materials for nanoparticle preparation is also a solution. For example, the surface of chitosan is positively charged and can be broken down by the colonic flora, which facilitates interaction with specific tissues and can be metabolized by the body. The biocompatibility and degradability of chitosan has been proven to be non-toxic at appropriate drug concentrations [ 128 ].

Difficulty in avoiding mononuclear phagocytic system (MPS)

In biofluids, NPs will adsorb proteins to form a corona layer referred to as “protein corona” in a broader sense giving biological identity to NPs and alters their biological characters, which will attract MPS especially macrophages to uptake NPs [ 129 ]. In order to avoid being uptaken by MPS, various polymer coatings such as forpolyether, polybetaine (PB) and polyolhave were investigated to cover NPs. For example, polyglycerol-grafting NPs are able to evade macrophage uptake by reducing protein adsorption [ 130 ]. In addition, there are two types of tumor-associated macrophages (TAM), M1 and M2. M1 macrophages inhibit tumor growth while M2 macrophages promote tumor growth. Therefore, no longer avoiding macrophages, but designing NPs targeted by macrophages, by regulating the function of macrophages, and even using macrophages as new drug carriers to exert anti-tumor effects may become a novel solution. At present, common design strategies for such NPs include inhibiting macrophage recruitment, depleting TAM, reprogramming TAMs, and blocking CD47-SIRPα pathway [ 131 ]. Among them, following the design concept of reprogramming or blocking CD47-SIRPα pathway, NPs that repolarize M2 macrophages to M1 type have made a breakthrough in vivo experiments [ 132 ].

Considering the above difficulties and referencing to advanced researches, we come up with a new possible design of NPs. The NPs skeleton is made of pyrolytic material (spirulina, exosomes, et al.). Then, photothermal materials (Au, Pd, etc.) are deposited on the NPs skeleton through electroless plating. After that the superparamagnetic iron oxide will be loaded on the surface of NPs through the sol–gel method. Then, suitable polymers (polybetaine, polyglycerol, etc.) will coat the NPs. Finally, drug (like doxorubicin) will be loaded on the NPs. Afterwards, under the guidance of PACT, NPs will be injected into the upstream of tumor supplying blood vessel, and the tumor will be irradiated with NIR. At the same time, three-dimensional magnetic field control is given to maximize the accumulation of NPs at the tumor site. Through this design, a large number of NPs will accumulate at the tumor site to ensure the drug concentration and PTT effect. At the same time, most NPs will be decomposed at the tumor site, and only a small number of NPs will circulate in the body.

Nowadays, anti-tumor therapy with NPs as the main body is still in the exploratory stage, and related technologies and equipments need to be invented, so it is unlikely to be clinically used in the short term. However, NPs can change part of the function or structure of many actual technologies. The upgrade of actual technologies is expected to be applied in clinic quickly, which contributes to upgrading the diagnosis and treatment of tumors in consequence. For example, NPs can help to develop electrochemical devices based on the interaction between ions and conductive polymers, such as organic electrochemical transistors (OFETs), electrolyte gated field-effect transistors (FETs), fin field-effect transistor (FinFETs), tunneling field-effect transistors (TFETs), electrochemical lab-on-chips (LOCs) [ 133 ]. These electrochemical devices are widely used in various tumor testing and diagnostic equipment. The use of NPs can help improve the accuracy of the equipment and reduce the detecting time. Many studies indicate that medical equipment using electronic components upgraded by NPs have been applied clinically [ 133 , 134 , 136 ].

Based on the evidence cited above, future research of NPs may not only focus on NPs themselves but also consider a feasible administration and efficacy assessing platform. In addition, the platform needs to be able to monitor immunotoxicity, the long-term toxicity, and neurotoxicity of NPs. As nanotechnology develops, if these problems were solved, NPs would be an ideal approach to upgrade cancer therapy and diagnosis.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Abbreviations

Nanoparticles

Photodynamics therapy

  • Photothermal therapy

Plasmon resonance effect

Gold nanorods

Surface-initiated atom transfer radical polymerization

N-isopropylacrylamide

Mesoporous silica nanoparticles

Ultrasmall manganese oxide

Gemcitabine

Oxygen/indocyanine green-loaded lipid nanoparticles

Photoacoustic

Magnetic particle imaging

Magnetic resonance imaging

Superparamagnetic iron oxide

Ultra-small SPIO

Optical coherence tomography

Magnetomotive optical coherence tomography

Monoclonal antibody

Doxorubicin

5-Fluorouracil

Reactive oxygen species

Enhanced permeability and retention effect

Epidermal growth factor receptor

Berberine hydrochloride

Antifreeze protein

Phase change materials

3D printed coplanar template

Amino-rich red emissive carbon dots

Covalent organic framework

Indocyanine green

Serum albumin

Multidrug resistance

Multidrug resistance-associated protein 1

P-glycoprotein

Photosensitizing substances

Up-conversion

Radiotherapy

Poly(lactic-co-glycolic acid)

Photoacoustic computed tomography

Mononuclear phagocytic system

Polybetaine

Tumor-associated macrophages

Organic electrochemical transistors

Electrolyte gated field-effect transistors

Fin field-effect transistor

Tunnelling field-effect transistors

Electrochemical lab-on-chips

Liu Y, Bhattarai P, Dai Z, Chen X (2019) Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer. Chem Soc Rev 48:2053–2108

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Acknowledgements

(1) National Key R&D Program of China (2018YFC1705102), which supported by Biological Center of Ministry of Science and Technology of China. (2) Capital Health Development Research Project (CFH2018-1-4201), which supported by Beijing Municipal Science and Technology Commission. (3) New Innovation Project-Yiqilin Leading Talent Project, which supported by Beijing Yizhuang Economic Development Zone Government. The fund doesn’t have code.

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Zhongyang Yu and Lei Gao are co-first authors.

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Oncology Department, Dongfang Hospital, Beijing University of Chinese Medicine, Fangguyuan Rd, Fengtai District, Beijing, 100078, China

Lei Gao, Quanwang Li & Kaiwen Hu

College of Engineering, China Agricultural University, Tsinghua East Rd, Haidian District, Beijing, 100083, China

Kehan Chen & Wenqiang Zhang

Department of Management, Fredericton Campus, University of New Brunswick, 3 Bailey Drive, Fredericton, NB, E3B 5A3, Canada

Qihang Zhang

Beijing University of Chinese Medicine, 11 North Third Ring East Road, Chaoyang District, Beijing, 100029, China

Zhongyang Yu

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ZY: Writing- Original draft preparation. ZY and KC: Performed the Literature Search of the Databases. LG: Writing- Reviewing and Editing. QZ: translation. QL and WZ: investigation. KH: Supervision. All authors read and approved the final manuscript.

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Yu, Z., Gao, L., Chen, K. et al. Nanoparticles: A New Approach to Upgrade Cancer Diagnosis and Treatment. Nanoscale Res Lett 16 , 88 (2021). https://doi.org/10.1186/s11671-021-03489-z

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March 27, 2024

Purdue researchers create biocompatible nanoparticles to enhance systemic delivery of cancer immunotherapy

YoonNanoparticles

Purdue University researchers are developing and validating patent-pending nanoparticles (left) to enhance immunotherapy effects against tumors. The nanoparticles are modified with adenosine triphosphate, or ATP, to recruit dendritic cells (right), which are immune cells that recognize tumor antigens and bring specialized immune cells to fight off tumors. (Images provided by Yoon Yeo)

PLGA nanoparticles modified with ATP slowly release anti-cancer drugs and recruit immune cells to fight tumors

WEST LAFAYETTE, Ind. — Purdue University researchers are developing and validating patent-pending poly (lactic-co-glycolic acid), or PLGA, nanoparticles modified with adenosine triphosphate, or ATP, to enhance immunotherapy effects against malignant tumors.

The nanoparticles slowly release drugs that induce immunogenic cell death, or ICD, in tumors. ICD generates tumor antigens and other molecules to bring immune cells to a tumor’s microenvironment. The researchers have attached ATP to the nanoparticles, which also recruits immune cells to the tumor to initiate anti-tumor immune responses. 

Yoon Yeo leads a team of researchers from the College of Pharmacy , the Metabolite Profiling Facility in the Bindley Bioscience Center , and the Purdue Institute for Cancer Research to develop the nanoparticles. Yeo is the associate department head and Lillian Barboul Thomas Professor of Industrial and Molecular Pharmaceutics and Biomedical Engineering; she is also a member of the Purdue Institute for Drug Discovery and the Purdue Institute for Cancer Research.

The researchers validated their work using paclitaxel, a chemotherapy drug used to treat several types of cancers. They found that tumors grew slower in mice treated with paclitaxel enclosed within ATP-modified nanoparticles than in mice treated with paclitaxel in non-modified nanoparticles.

“When combined with an existing immunotherapy drug, the ATP-modified, paclitaxel-loaded nanoparticles eliminated tumors in mice and protected them from rechallenge with tumor cells,” Yeo said.

The research has been published in the peer-reviewed journal ACS Nano .

Challenges to systemic immunotherapy delivery

Immunotherapy is a promising approach to fighting cancer, but Yeo said it does not benefit a large population of patients because they do not have the powerful immune cells needed to combat tumors. 

“Pharmacological agents to activate immune cells can directly be given to tumors,” Yeo said. “Then the immune system can fight not only the treated tumors but also nontreated tumors in distant locations as the activated immune cells circulate in the bloodstream.”

However, Yeo said most tumors with poor prognoses are not always locatable or accessible. Therefore, they may not be effectively treated by local therapy. She and her team envisioned systemic delivery of immunotherapy, but there are challenges.

“For successful systemic administration, active ingredients that stimulate anti-tumor immune responses need to be simultaneously present in tumors to exert concerted effects on the target,” Yeo said. “The ingredients also must maintain their activity until they reach tumors, but not cause toxic off-target effects. Moreover, the carriers traditionally used in local drug delivery offer limited utility in systemic application because they may not be compatible with blood components.” 

Yeo and her colleagues used biocompatible polymeric nanoparticles to deliver immunotherapy compounds and modified them to safely activate the immune system. 

“We employed poly (lactic-co-glycolic acid), or PLGA, nanoparticles based on the strong track record of the polymer in FDA-approved products and its routine use in the systemic delivery of poorly water-soluble drugs,” Yeo said.

Tests verified the ATP-modified PLGA nanoparticles were well tolerated in mice upon multiple systemic injections. They were able to recruit dendritic cells, the immune cells that recognize tumor antigens and bring specialized immune cells to fight off tumors. 

“Moreover, the nanoparticles were shown to control the release of paclitaxel to minimize its systemic toxicity,” Yeo said.

The next development steps

Yeo and her colleagues will continue their work on the ATP-modified nanoparticles.

“We are currently working on improving the delivery of the nanoparticles to tumors and combining them with other treatments that will circumvent the resistance to the nanoparticle-delivered immunotherapy,” Yeo said. “To finance these efforts, we will apply for continued support from the National Institutes of Health. We are also open to industry partnerships to take this technology to the clinic.”

Yeo disclosed the nanoparticles innovation to the Purdue Innovates Office of Technology Commercialization , which has applied for a patent from the U.S. Patent and Trademark Office to protect the intellectual property. Industry partners interested in developing the compound or commercializing it for the marketplace should contact Joe Kasper, assistant director of business development and licensing — life sciences, at [email protected] , about track code 69546 .

Yeo and the research team received funding from the National Institutes of Health, the National Center for Advancing Translational Sciences, the Indiana Clinical and Translational Sciences Institute, and the Purdue Institute for Cancer Research.

About Purdue University

Purdue University is a public research institution demonstrating excellence at scale. Ranked among top 10 public universities and with two colleges in the top four in the United States, Purdue discovers and disseminates knowledge with a quality and at a scale second to none. More than 105,000 students study at Purdue across modalities and locations, including nearly 50,000 in person on the West Lafayette campus. Committed to affordability and accessibility, Purdue’s main campus has frozen tuition 13 years in a row. See how Purdue never stops in the persistent pursuit of the next giant leap — including its first comprehensive urban campus in Indianapolis, the new Mitchell E. Daniels, Jr. School of Business, and Purdue Computes — at https://www.purdue.edu/president/strategic-initiatives .

About Purdue Innovates Office of Technology Commercialization

The Purdue Innovates Office of Technology Commercialization operates one of the most comprehensive technology transfer programs among leading research universities in the U.S. Services provided by this office support the economic development initiatives of Purdue University and benefit the university’s academic activities through commercializing, licensing and protecting Purdue intellectual property. In fiscal year 2023, the office reported 150 deals finalized with 203 technologies signed, 400 disclosures received and 218 issued U.S. patents. The office is managed by the Purdue Research Foundation, which received the 2019 Innovation & Economic Prosperity Universities Award for Place from the Association of Public and Land-grant Universities. In 2020, IPWatchdog Institute ranked Purdue third nationally in startup creation and in the top 20 for patents. The Purdue Research Foundation is a private, nonprofit foundation created to advance the mission of Purdue University. Contact [email protected] for more information.

Writer/Media contact: Steve Martin, [email protected]

Source: Yoon Yeo, [email protected]

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  6. Takeaway: nanoparticles to the rescue

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  1. Nanoparticles: Properties, applications and toxicities

    Nanotechnology is a known field of research since last century. Since "nanotechnology" was presented by Nobel laureate Richard P. Feynman during his well famous 1959 lecture "There's Plenty of Room at the Bottom" (Feynman, 1960), there have been made various revolutionary developments in the field of nanotechnology.Nanotechnology produced materials of various types at nanoscale level.

  2. Nanoparticles

    Nanoparticles articles from across Nature Portfolio. Atom; RSS Feed; Definition. Nanoparticles are particles that exist on a nanometre scale (i.e., below 100 nm in at least one dimension).

  3. A review on nanoparticles: characteristics, synthesis, applications

    2.2. Discovery of C, Ag, Zn, Cu, and Au nanoparticles. Carbon NPs were found in 1991, and Iijima and Ichihashi announced the single-wall carbon nanotube synthesis with a diameter of 1 nanometer in 1993 (Chen et al., 2021).Carbon nanotubes (CNTs), also known as Bucky tubes, are a kind of nanomaterial made up of a two-dimensional hexagonal lattice of carbon atoms.

  4. Nanoparticles

    A total-synthesis framework for the construction of high-order colloidal hybrid nanoparticles. Colloidal hybrid nanoparticles represent an emerging class of multifunctional artificial molecules ...

  5. Research articles

    Read the latest Research articles from Nature Nanotechnology. ... research articles. Research articles. Filter By: Article Type. All. All; Analysis (8) Article (1132) Letter (1032) Matters Arising ...

  6. Articles

    A way to prepare magnetically separable palladium nanocatalysts active in Heck reaction—SI-RAFT/MADIX polymerization for modification of magnetic nanoparticles. Iwona Misztalewska-Turkowicz. Sławomir Wojtulewski. Agnieszka Z. Wilczewska. Research 26 February 2024 Article: 44.

  7. Home

    Journal of Nanoparticle Research is a peer-reviewed journal that delves into concepts, properties, phenomena, and processes of structures at the nanoscale. Covered topics include synthesis, assembly, transport, reactivity, and stability of nanoscale structures. Features applications, structures, and devices with novel functions via precursor ...

  8. EGCG-based nanoparticles: synthesis, properties, and applications

    Notably, the non-covalent and covalent interactions of EGCG with other substances significantly contribute to the improved properties of these nanoparticles. EGCG-based nanoparticles appear to have a wide range of applications in different industries, but further research is required to enhance their efficacy and ensure their safety.

  9. Gold nanoparticles: Synthesis properties and applications

    In recent years, nanotechnology has been the topic of extensive research and a great deal of interest among researchers. The manufacturing and utilization of nanoparticles (NPs) has expanded dramatically as a result of the rapid development of nanotechnology. Gold nanoparticles (AuNPs) are one of the most important nanoparticles, and they have ...

  10. Nanoparticles in Drug Delivery: From History to Therapeutic

    Current research into the role of engineered nanoparticles in drug delivery systems (DDSs) for medical purposes has developed numerous fascinating nanocarriers. ... Web of Science published more than 1000 nanomedicine articles in 2015 and most of the articles relating nanoparticles (NPs) for biomedical usage . Nanocarriers such as dendrimers ...

  11. Magnetic Nanoparticles: From Design and Synthesis to Real World

    3.3. Other Magnetic Nanoparticles. In typical applications ultrafine superparamagnetic particles based on Fe 3 O 4 and γ-Fe 2 O 3 are commonly used. Meanwhile other magnetic particles are studied and used exceptionally (except for the above-mentioned and rarely used particles containing cobalt).

  12. Green synthesis of nanoparticles: Current developments and limitations

    In this review, processes involved in the green synthesis of nanomaterials were summarized, and the relevant limitations were evaluated. This review hopes to point out the major issues and challenges in green synthesis of nanoscale metallic nanoparticles, and put forward the prospects for future research direction.

  13. Improved CaP Nanoparticles for Nucleic Acid and Protein Delivery to

    Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). ... (L-lysine) (PLL). CaP nanoparticles significantly improved transfection with plasmid DNA encoding enhanced green fluorescent protein (eGFP) in pre-osteoblastic MC3T3-E1 cells ...

  14. Cu and Cu-Based Nanoparticles: Synthesis and Applications in Catalysis

    The applications of copper (Cu) and Cu-based nanoparticles, which are based on the earth-abundant and inexpensive copper metal, have generated a great deal of interest in recent years, especially in the field of catalysis. The possible modification of the chemical and physical properties of these nanoparticles using different synthetic strategies and conditions and/or via postsynthetic ...

  15. A bibliometric analysis of the role of nanotechnology in dark

    Most cited articles in the research field. To understand the effect of nanoparticles on dark fermentative H 2 production, it is important to analyze and study the most cited articles related to that topic. In web of science data base, there are two types of citations: (1) global citations and (2) local citations.

  16. Nanoparticles

    Nanoparticle asymmetry shapes an immune response. The chirality, or handedness, of nanoparticles is shown to be a key factor in determining how well such particles engage with the immune system ...

  17. Multicolor Long-Term Single-Particle Tracking Using 10 nm Upconverting

    Movie S1 showing multicolor long-term single-particle tracking using 10 nm upconverting nanoparticles corresponding to panels shown in Figure 5 . nl4c00207_si_001.pdf (2.25 MB) nl4c00207_si_002.avi (14.88 MB) ... Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that ...

  18. Antibody‐Conjugated Magnetic Nanoparticle ...

    Research Article. Open Access. Antibody-Conjugated Magnetic Nanoparticle Therapy for Inhibiting T-Cell Mediated Inflammation. Mahbub Hasan, ... Nanoparticle tracking analysis (NTA) measures the Brownian motion of nanoparticles by analyzing the movement of laser-beam-illuminated particles. The diffusion coefficient reflects the random ...

  19. Advances in lipid nanoparticle mRNA therapeutics beyond COVID-19

    The remarkable success of two lipid nanoparticle-mRNA vaccines against coronavirus disease (COVID-19) has placed the therapeutic and prophylactic potential of messenger RNA (mRNA) in the spotlight. It has also drawn attention to the indispensable role of lipid nanoparticles in enabling the effects of this nucleic a Recent Review Articles Nanoscale 2024 Emerging Investigators

  20. Researchers create biocompatible nanoparticles to ...

    The nanoparticles slowly release drugs that induce immunogenic cell death, or ICD, in tumors. ICD generates tumor antigens and other molecules to bring immune cells to a tumor's microenvironment.

  21. Nanoparticles for Cancer Therapy: Current Progress and Challenges

    Nanoparticles. Nanoparticles (NPs) are technically defined as particles with one dimension less than 100 nm with unique properties usually not found in bulk samples of the same material [].Depending on the nanoparticle's overall shape, these can be classified as 0D, 1D, 2D or 3D [].The basic composition of nanoparticles is quite complex, comprising the surface layer, the shell layer, and the ...

  22. Microalgae as a potential natural source for the green synthesis of

    In the last few years, a new frontier has opened up at the interface of biotechnology and nanotechnology. This new frontier could help microalgae-based nanomaterials to possess new functions and abilities. Processes for the green synthesis of nanomaterials are being investigated, and the availability of biological resources such as microalgae ...

  23. (PDF) Current Research on Silver Nanoparticles: Synthesis

    Silver nanoparticles have tunable physical and chemical properties, so it has been studied widely to improve its applicability. The antimicrobial properties of Ag NPs are finding their application ...

  24. Frontiers

    The culture filtrate of Hypocrea lixii GGRK4 played a vital role as a reducing and stabilizing agent in the myco-synthesis of AgNPs using silver nitrate (AgNO3). The extracellular extract derived from fungi emerged as a noteworthy option for synthesizing silver nanoparticles (AgNPs) due to its potential composition of metabolites, including enzymes and other bioactive substances. Hence, the ...

  25. Nanoparticles

    Read the latest Research articles in Nanoparticles from Nature Nanotechnology. ... Nanoparticles articles within Nature Nanotechnology. Featured. Review Article | 21 March 2024.

  26. Accelerating CAR T cell therapy: Lipid nanoparticles speed up

    Antigen Presenting Cell Mimetic Lipid Nanoparticles for Rapid mRNA CAR T Cell Cancer Immunotherapy. Advanced Materials , 2024; DOI: 10.1002/adma.202313226 Cite This Page :

  27. Nanoparticles: A New Approach to Upgrade Cancer Diagnosis ...

    Traditional cancer therapeutics have been criticized due to various adverse effects and insufficient damage to targeted tumors. The breakthrough of nanoparticles provides a novel approach for upgrading traditional treatments and diagnosis. Actually, nanoparticles can not only solve the shortcomings of traditional cancer diagnosis and treatment, but also create brand-new perspectives and ...

  28. A critical review on silver nanoparticles: From synthesis and

    Metallic silver is a naturally available soft, white, lustrous rare element with high thermal and electrical conductivity (Wijnhoven et al., 2009; Lansdown, 2010; Liu and Jiang, 2015).Silver nanoparticles are a special form of metallic silver having less than 100 nm size in at least one dimension which offers silver nanoparticles a high surface area to volume ratio (Pulit-Prociak et al., 2015 ...

  29. Purdue researchers create biocompatible nanoparticles to enhance

    The nanoparticles slowly release drugs that induce immunogenic cell death, or ICD, in tumors. ICD generates tumor antigens and other molecules to bring immune cells to a tumor's microenvironment. The researchers have attached ATP to the nanoparticles, which also recruits immune cells to the tumor to initiate anti-tumor immune responses.

  30. Nanoparticles developed at UTSW effectively fight tumors

    DALLAS - March 21, 2024 - A nanoparticle-based therapy developed by UT Southwestern Medical Center scientists stimulated an immune pathway that eradicated tumors in mouse models of various cancer types. Their findings, published in Science Immunology, offer a new way to potentially harness the power of the body's immune system against cancer.