1 INTRODUCTION

Cancer is a diseased condition that involves a complex pathophysiology and is the most prevalent and leading cause of mortality in the world.¹ Nowadays, the screening and development of potential anticancer agents is an absolute necessity. In this regard, metal-based nanomaterials (NMs) have potential to be antitumor agents, against a wide range of cancerous cells. NMs are defined as the materials with dimensions less than 100 nm.² Several investigations have been conducted for the development of NMs in various shapes and sizes, such as nanotubes, nanoparticles (NPs), fibers, wires, and nanodots, depending upon the various diseases. NMs significantly improved the diagnosis and treatment of diseases via delivery systems, imaging, and photothermal agents due to their unique characteristics.³

Metal-based NPs, such as gold and silver, have been frequently used in DNA hybridization detection, cell imaging, protein interaction, and photothermal therapy (PTT).⁴ The remarkable optical characteristics, accessible surface chemistry, and correct size scale enable silver and gold (AuNPs) highly promising for cancer diagnostic and therapeutic applications. Optimizing the size and shape of metal-based NPs or conjugating them with certain ligands/biomarkers can enhance the cancer diagnosis and treatments.²

Drug delivery systems (DDSs) based on NMs have been shown to improve the therapeutic efficacy of anticancer treatments and minimize the side effects.^{5, 6} Several complications like inadequate tumor penetration capacity, inappropriate and nonspecific accumulation in tissues, early drug release into tissues, and unregulated drug release at the target location can be overcome depending upon the DDSs that were successfully investigated in human and animal models in both experimental and preclinical conditions.⁷

NPs based DDSs have considerable potential for the treatment of several types of cancer.⁸ The important technological advantages of NPs are they can be used as drug carriers with high carrier capacity, high stability, and feasibility in both hydrophobic and hydrophilic substances and can be used in various routes of administration, for example, oral application and inhalation route.⁹ NPS can also be designed to allow controlled drug release from the matrix. These properties of NPs enable the improvement of drug bioavailability and reduction of the dosing frequency and may resolve the problem of nonadherence to cancer therapy.¹⁰ Materials such as polymers, either natural (like gelatin or albumin) or synthetic (such as polylactides or poly(alkyl cyanoacrylates)), or solid lipids are used to make biocompatible and biodegradable NPs. Drugs contained in NPs are typically released from the matrix in the body through swelling, diffusion, erosion, or degradation.¹¹ The field of cancer diagnosis and therapy has undergone various changes with the development of nanotechnology.¹² The use of NPs (1–100 nm) in the treatment of cancer due to their drug-like properties, such as stability, reduced toxicity, biocompatibility, enhanced permeability along with retention effect, and specificity.¹³ The NPs DDs is particular and utilizes tumor and tumor environment characteristics. NPs are able to overcome multidrug resistance in addition to the shortcomings of traditional cancer treatment.¹⁴ Several NMs are employed in cancer diagnosis given in Table 1.

There has been a lot of research done on different metallic NPs for biomedical uses.⁴⁰ Due to their noteworthy inertness, nanoscale architectures, and sizes that are comparable to many biological molecules, they are of great interest in the biomedical area.⁴¹ Numerous applications in various areas of biomedicine have resulted from their intrinsic properties, which include electronic, optical, physicochemical, and surface plasmon resonance and can be changed by altering particle characteristics like size, shape, environment, aspect ratio, and ease of synthesis.⁴² These include photothermal and photodynamic therapy (PDT), imaging, sensing, targeted medication delivery, and the regulation of two or three applications.⁴³ The current review highlights metal-based NMs that have been reported for cancer applications. The purpose of this review is to explore the potential of NMs in cancer therapy so that new drugs can be developed for the diagnosis and treatment of cancer. We have also focused on plant-based NMs that can be utilized in cancer treatment. This review article aims to inspire researchers to develop innovative approaches in the field of metal-based NMs for cancer treatment and diagnosis. By highlighting the potential of these materials in various applications, such as drug delivery, imaging, and PTT, the article encourages researchers to explore and develop new strategies to enhance the potency and efficacy of metal-based NMs. Ultimately, this could lead to the development of more effective and targeted cancer therapies, improving outcomes for patients.

2 APPLICATIONS OF METAL-BASED NMS IN DIFFERENT TYPES OF CANCER

NMs hold a lot of promise to identify and eliminate cancer cells along with the potential to eradicate malignant cells with minor casualties to surrounding tissue.⁴⁴ In terms of healthcare, there is growing optimism that NMs will lead to substantial advancements in illness treatment and detection. Researchers have been driven to create new nano-platforms that can execute both activities at the same time as a result of these lofty ambitions. As a result, a new multidisciplinary study topic called theranostics has emerged. Iron-based graphene oxide (GO), metal oxide magnetic nanocrystals, manganese dioxide (MnO₂), black phosphorus, MXene, and palladium (Pd) are examples of theranostic NMs.⁴⁵

NMs also assisted in the minimization of toxicity, optimization in targeting, maximizing the bioactivity, and offering a flexible way to modify the release of the encapsulated drug moiety.⁴⁶ Meanwhile, inorganic NMs of different metals like Au, Ag, Fe, Ce, Se, Zn, and Ti are also used for their unique bioactivities in nanoforms. Tumor imaging plays an essential function in the detection and treatment of cancers like mammography. Potential applications of different NMs used in cancer therapy are given in Table 2.⁴⁷

2.1 Transition metal nanosheets

Nanosheets are made up of different metals that have various applicabilities in different fields, such as chemotherapy,⁷¹ significant photothermal conversion efficiency, intensive near-IR absorption, magnetic properties, and strong X-ray attenuation properties.⁷² Different contrast agents, and transition metals, have been studied so far, because of their distinctive optical characteristics and low toxicity.⁷³ The nanocomposites (NCs) are also reported to have an outstanding absorption in the near-infrared region (NIR). Photoluminescence imaging has substantial implications for several transition metal NCs with small lateral dimensions.⁷⁴ Transition metal NCs made up of large-atomic-number elements that had a high X-ray absorption potential and might be used in computed tomography.

Transition metal dichalcogenides (TMDCs) have recently gained a lot of interest in nanomedicine because of their remarkable characteristics. A bottom-up solution-phase approach has been used to synthesize titanium disulfide (TiS₂) nanosheets, a novel TMDC NM, which is modified using polyethylene glycol (PEG) and developed as TiS₂-PEG with good physiological stabilization and low in vitro toxicity.⁷⁶

The crystallinity of NMs is an important factor in determining their quality; however, measuring the crystal structures of thin TMDC nanosheets of 10 nm via standard in-plane X-ray diffraction (XRD) is difficult, and high-resolution electron microscopy is usually required to directly determine these features. Due to their strong absorbance in the NIR, in photoacoustic imaging, TiS₂-PEG nanosheets could provide a significant contrast that showed the high tumor uptake. A pictorial diagram of the conventional 2D materials available for the cancer theranostics, and their oncological applications is given in Figure 1.⁷⁷ In the field of cancer imaging, the use of NMs as contrast agents has garnered significant attention due to their unique properties. NMs can enhance the sensitivity and specificity of various imaging techniques, such as magnetic resonance imaging (MRI), CT, and PET. They can be engineered to specifically target cancer cells, thereby minimizing the risk of false-positive results. QDs are an example of NMs that emit bright and stable fluorescence, making them ideal for optical imaging. Iron oxide NPs (IONPs), on the other hand, can be used as contrast agents for MRI and are biocompatible. AuNPs are highly biocompatible and can be functionalized with targeting molecules for both optical and CT imaging. Carbon nanotubes are highly sensitive contrast agents for both MRI and PET imaging. NMs have the potential to revolutionize cancer imaging by improving imaging techniques’ accuracy and specificity, leading to better diagnosis and treatment outcomes. They can also be utilized for targeted drug delivery, which can improve the efficacy of cancer treatment while minimizing side effects. Potential applications of different NMs used in cancer imaging are given in Table 3.

TABLE 3. Nanomaterials (NMs) used in the imaging of cancer.

Nanomaterial	Application	In vivo	In vitro	Physical property	Delivery	Reference
AuNPs	Early-stage therapy monitoring	No data	Support	FRET	No data	78
AuNPs	Raman spectroscopy tags	Support	No data	Surface-enhanced Raman scattering	Intravenous injection active targeting (anti-EGFR)	79
AuNPs	Spectral-domain optical coherence tomography	Support	No data	Strong scattering	Local injection active targeting (anti-EGFR)	80
AuNPs	X-ray contrast agents	Support	No data	Opaque to X-rays	Intravenous injection	81
192Au colloids	Radio-labeling	Support	No data	Radioactivity	No data	82
Gold nanocages	No data	Support	No data	SPR in NIR range	Intradermal injection	83
Magnetic/Au core/shell NPs	No data	Support	No data	Magnetism	Local injection	84
Magnetic NPs	MRI marker	Support	No data	Magnetism	Intravenous injection active targeting (anti-HER2)	85
Nanoshell magnetic NPs	No data	No data	Support	Magnetism of magnetic NPs	Active targeting (anti-HER2)	86
Paramagnetic NPs	No data	Support	No data	Magnetism	Active targeting	87
QDs	Lymph node tracers	Support	No data	NIR fluorescence	Intradermal injection	88
QDs	Cancer imaging	Support	No data	Photoluminescence	Intravenous injection active targeting	89

2.5 Gold nanoparticles

AuNPs have been widely explored due to their remarkable biological and optical properties and can be employed for gene and drug delivery,¹¹² as well as for the diagnostic, thermal ablation, and radiation augmentation purposes.¹¹³ Several chemicals are now being tested for possible medication delivery, especially in the treatment of cancer. The ability to change the surface of AuNPs with various targeting and functional chemicals significantly increases the variety of potential biological applications, with a focus on anticancer therapy. AuNPs have been reported to increase the solubility and retention time in blood, to help in the transportation of drugs, and control the release patterns of the therapeutics.¹¹⁴

Functionalized AuNPs have exceptional biocompatibility and predictable bioavailability characteristics that make them an excellent choice to deliver novel therapeutics.⁵² AuNPs used in PTT are controlled due to their unique shape, size, structure, and, most significantly, photothermal characteristics.¹¹⁴

Gold nanorods (AuNRs) with different widths and lengths can affect the absorption and scattering band from visible to NIR. Thickness and core radius of AuNPs can produce a comparable result.¹¹⁶ This allows the development of AuNRs and gold nanoshells (AuNSs) with unique properties according to the tumor's size and location.¹¹⁷ Furthermore, the aggregations of AuNPs have been found to have a considerable influence on both optical and thermal characteristics.¹¹⁸ A pictorial diagram with the concept of AuNPs in the cancer treatments is provided in Figure 2.¹¹⁹

Multifunctional nano platforms that integrate therapeutic elements and multidisciplinary imaging are the future of nanomedicine.¹²⁰ The ultimate goal for NP-based medicines is to enable efficient, specific in vivo drug delivery without systemic toxicity, with the dose given, and therapeutic efficacy over time.¹²¹

Functionalized AuNPs with therapeutic and targeted peptides could be a promising anticancer nanosystem for improving therapeutic drug efficacy.¹²² To avoid filtration in the spleen, the size of AuNPs must be less than 150 nm. The particles should be larger than 15 nm to avoid fast clearance by the kidneys; hence, 90 nm is in the proper size range. For AuNPs, the best size is reported around 90 nm for cell targeting.¹²³ DDSs of this sort can be designed to carry one or more medications as well as many targeting compounds as therapeutic and diagnostic NPs for imaging and therapeutic purposes.¹²⁴ AuNPs have been used in several applications, such as delivery, therapy, imaging, and diagnostics application given in Figure 3.

3 SILICON DIOXIDE NANOPARTICLES

Silicon dioxide (SiO₂NPs) are commonly utilized in biomedicines for different diseases such as cancer as well as consumer items, including cosmetics and sunscreens.¹⁷⁷ SiO₂NPs may be useful for the development of potential nanomedicine due to their unique structure, a size that incorporates several functions to utilize optical properties. SiO₂NPs can be used in optical imaging due to their different optical characteristics at the micro-, nano-, and in vivo levels using both visible and NIR.¹³⁴ However, depending on the size and concentration of NPs, SiO₂NPs can have some harmful impacts on human health.

SiO₂NPs with a thyroid-stimulating hormone receptor-targeting ligand can effectively target thyroid malignancy.¹⁷⁸ In vivo, SiO₂NPs reduce tumor size while having fewer harmful side effects. This study lays the door for efficient thyroid cancer chemotherapy.¹⁷⁹ The cytotoxic effect of SiO₂NPs was evaluated on MCF-7 cell lines by increasing the concentration of NPs. The apoptosis rate was found to be increased, and the proliferation rate was reduced.¹⁸⁰ In this study, antitumor effects of SiO₂NPs were found to be excellent and presented as good gene carriers for breast cancer. SiO₂NPs were also reported for the improved release rate of gene drugs and enhanced encapsulation efficiency. It has been observed that as increasing the concentration of SiO₂NPs, its effect on breast cancer cells was found to be increased, whereas the damage on the normal cell was minimum.¹⁸¹ This study suggested that SiO₂NPs may be an excellent targeted gene DDSs. Asiri et al. synthesized SiO₂NPs conjugated with (3-glycidyloxypropyl)trimethoxysilane (3GPS), and these NPs were characterized on the basis of size, morphology, SEM, thermogravimetric analysis, Fourier transform infrared spectroscopy (FTIR), and transmission electron microscopy (TEM).¹⁸² In this study, it was found that SiO₂NPs possess potential anticancer properties against colon cancer.¹⁸³

SiO₂NPs were also investigated on HCT-116 to evaluate their anticancer potential using an MTT assay. Results demonstrated that cancer cell viability and cell proliferation were found to be decreased, and SiO₂NPs caused cell death in a dose-dependent way. SiO₂NPs provide application in the therapy of certain diseases, in vivo imaging, and cancer diagnosis.¹⁸⁴ Further suggested that SiO₂NPs may have applications in photodynamic therapy, in which a lesion location is treated by irradiating it with light. The potential for SiO₂NPs to play an essential role in the integration of light-based diagnostics and treatments.¹⁷⁷

4 SELENIUM NANOPARTICLES

Selenium (Se) is a trace mineral used to develop selenium (SeNPs) that have gained importance in the research due to their potential anticancer properties.¹⁸⁵ Human dermal fibroblasts cells at quantities up to 1 ppm, the SeNPs demonstrate mild cytotoxicity while having anticancer activity on human melanoma as well as glioblastoma cells at the same range of concentrations.¹⁸⁶ Several selenoproteins contain oxidoreductase function and, hence, control the redox balance in the body. Se has limited treatment efficacy and narrow toxicity margins, but SeNPs have significantly reduced toxicity.¹⁸⁷

SeNPs have been studied for possible therapeutic benefits in a variety of oxidative stress. To the inflammation-mediated diseases, such as diabetes, cancer, nephropathy, and arthritis, and provide an acceptable transport platform for transporting various drugs to the point of activity,¹⁸⁸ SeNP-based techniques have shown promise in combating drug resistance and minimizing the side effects of chemotherapeutic drugs. SeNPs provide a great platform for transporting chemotherapeutic agents to the targeted area. In comparison to MDA-MB 231 cells, it also influences estrogen receptor signaling in MCF-7 cell lines that result in the enhanced production of cytochrome C, Bax, and P-p38.¹⁸⁹ In MCF-7 cells, SeNPs were found to have lower binding and promote apoptosis, necrosis, and decrease CD44 expression; they also caused disruption and deregulation of the cytoskeleton F-actin.¹⁹⁰ In fibrosarcoma cell lines, SeNPs decrease the production of matrix metalloprotein-2, which is associated with tumor invasion, metastasis, and angiogenesis. Xia et al. developed doxorubicin-based SeNPs for the treatment of non-small lung cancer cell lines.¹⁹¹ Modification of SeNPs was performed via the addition of cyclic peptide, Arg-Gly-Asp-d-Phe-Cys [RGDfC]. After the modification, doxorubicin drug was loaded, and the RGDfC-Se@DOX system was prepared for targeting cancer cell lines. Different characterizations such as TEM and FTIR were performed, and the sizes of the particles were found to be 18 nm, having 7–12 nm average spherical particle size. Flow cytometry was performed for the investigation of apoptosis induced in the A549 cell lines. The resulted RGDfC-Se@DOX system showed higher apoptosis as compared to the DOX and Se@DOX groups. This study concluded that the nano delivery system played a crucial role in the treatment of lung cancer.^{192, 193}

5 NANOCOMPOSITES WITH MULTIPLE APPLICATIONS

Nanocomposite (NC) materials are made up of many phases, each of which has at least one, two, or three nanometer-scale dimensions.¹⁹⁴ Understanding the structure–property relationship is directly influenced by the ratio of surface area to volume of reinforced material utilized during NCs synthesis.¹⁹⁵ NCs provide us with numerous ideas for addressing problems in a variety of fields, including healthcare, pharmaceuticals, food packaging, electronics, and energy.¹⁹⁶ The physical characteristics of the NCs could be useful to develop new and effective cancer-detecting sensors, tumor-imaging agents, and cancer treatment medicines.¹⁹⁷

Biocompatible polymers with inorganic NPs and natural or rationally designed biomolecules provide a path toward multifunctional composite systems.¹⁹⁸ Although just a few of these innovations have been tested in humans, NCs based on functionalized semiconductors and metal have the potential to improve the cancer diagnosis and treatment.¹⁹⁹ With the right composition, size, and 3D structure, NCs could be used as a powerful immune adjuvant system.

Zinc oxide NCs (ZnONCs) are rapidly taken up by antigen-presenting cells due to their excellent physical and chemical properties and decomposed to release intracellular Zn ions and, as a result, cause the formation of intracellular ROS.²⁰⁰ Toll-like receptors identify NCs, which effectively activate innate immune cells and drive pro-inflammatory responses. These NCs improve antigen-specific adaptive immune responses, such as antibody formation and T cell responses,²⁰¹ by activating antigen-presenting cells and delivering associated antigens into intracellular compartments. Various NPs capable of targeting the cell nucleus are given in Table 4.²⁰²

In vivo research using ZnONCs with distinct compositions produced encouraging proof of concept data for developing therapeutic vaccinations against infections and malignancies.²²¹ The use of NCs as vaccine delivery systems and immunotherapeutic agents is still in the early stages of research. Several difficulties are encountered, including challenges in mass-producing NCs with consistent functionalities and acceptable capabilities in a reproducible manner.²²² Due to a lack of expertise in nano–bio interfacial interactions, further research is needed to determine the possible toxicity and biodistribution of NCs during in vivo usage.

6 PLANT-BASED NANOMETAL IN CANCER

The benefits of employing plants to synthesize NPs are they remain effectively accessible, safe, and produce a variety of metabolites that may be useful in cancer treatment.²²² A variety of plants are presently being studied because of their significance in NPs synthesis.²²³ AuNPs were synthesized by using an alfalfa plant with a size range of 2–20 nm.²²⁴ Ag, Ni, Co, Zn, and Cu NPs also have been synthesized inside live Brassica juncea plants (Indian mustard), Helianthus annuus (sunflower), and Medicago sativa (Alfalfa).²²⁵ Several plants are known to aggregate metal concentrations that are higher in concentrations, in comparison to others; these are referred to as hyper-accumulators of the plants studied. The B. juncea exhibited a superior potential to accumulate metals and eventually assimilate them as NPs.²²⁶ A lot of work has been done recently in terms of plant-based reduction of metal NPs, as well as the significance of phytochemicals. The primary important phytochemicals have also been discovered as carboxylic acids, amides, aldehydes, ketones, flavones, and terpenoids in the wavelength of infrared spectroscopic studies.²²⁷ Flavones, quinones, and organic acids are the main water-soluble phytochemicals that contribute to immediate reduction.²²⁸ The phytochemicals present in Hydrilla sp. (hydrophytes), Bryophyllum sp. (xerophytes), and Cyprus sp. (mesophytes) and their significance in the synthesis of AgNPs are investigated.²²⁹ The Xerophytes were confirmed to have emodin, an anthraquinone that undergoes the tautomerization that leads to the productions of AgNPs.²³⁰ Catechol is reported to be converted into protocatechualdehyde and protocatechuic acid under alkaline environments. Reactions resulted in the liberation of hydrogen, and it was concluded that it was involved in the production of NPs.²³¹ The NPs synthesized using hydrophytes, mesophytes, and xerophytes were found to be in the size of 2–5 nm. Some of the plant-based NPs are listed in Table 5.²³²

7 THE EFFECT OF SIZE, SHAPE, AND SURFACE PROPERTIES OF NANOPARTICLES

Vascular permeability diminishes as the size of NPs increases.²⁴⁴ The tumor vesicles have different hole sizes depending on the type of tumor and where it is growing. For example, the pore diameters of malignancies in the cranial window are significantly smaller than those found in the dorsal chamber; the size of the NPs must be adjusted to the type and location of the tumor.²⁴⁵ The shape, size, and core chemical characteristics of NPs are all important factors in cellular uptakes, like spherical, cubic, rod shape, or worm shape, which have a significant impact on cellular uptake and anticancer properties.²⁴⁶ When cubic, spherical, and rodlike AuNPs are compared, spherical NPs found to have the higher uptake in terms of weight, and rod-shaped NPs demonstrate the large uptake in terms of quantity.²⁴⁷ The circulation period improved as the size of AuNPs increased from 5 to 25 nm. NPs aggregate into solid tumors in cancer treatment by utilizing the enhanced permeability and retention (EPR) effect.²⁴⁸ However, the circulation time of NPs has a major impact on EPR. Large NPs have significantly longer circulation durations, which enables them to take advantage of the EPR effect. Therefore, for NPs that rely on the EPR effect to localize to tumors, particle size is important. A pictorial diagram of different shapes of AuNPs along with similar sizes and similar shapes along with different sizes targeting cancer cells is given in Figure 4.²⁴⁹

The 50 nm size of AuNPs also affects cellular uptake due to their influence on the entropic and enthalpic characteristics, which control the efficiency of AuNPs adherence to cellular receptors.²⁵⁰ It has been found that AuNPs with a size of 50 nm demonstrated the highest cellular uptake, which is required for chemotherapies.²⁵¹ Spherical and smaller NPs resulted in deeper, more uniform penetration inside the solid tumor, and the shape and size ratio of NPs may be important parameters in the development of better penetrating, more efficient, nano-carriers for cancer therapies.²⁵² The anticancer efficiency of AuNPs was found to be in increasing order: stars, rods, and triangles. The mechanisms of cellular uptake of AuNPs were investigated and found that several sizes and shapes of AuNPs tended to use different endocytosis pathways.²⁵³ Triangle AuNPs were found to be more effective than other NPs; the size limit of 30 nm for spherical AuNPs indicates that NPs smaller than 30 nm are not effective to drive the membrane process. AuNPs in the size range of 2–100 nm decorated with Herceptin were found to be effective in breast cancer.²⁵⁴

Due to the size limitation of the NPs, a size of 60 nm in diameter results in a shortage of receptors, and size below 10 nm is found to be rapidly eliminated.²⁵⁵ Several studies reported that NPs with smaller size and rod shapes have higher binding potential due to larger contact areas and smaller drag forces.²⁵⁶ In the in vivo environment, AuNPs with different sizes and shapes interact in a different way, and several studies demonstrated that spherical AuNPs can improve interaction with the immune system and stimulate toxicity, due to the similarity in shape and size of pathogenic microorganisms. When considering the entry of AuNPs in the cells, both shape and size will be very essential.²⁵⁷

Cell receptors are found to be in different shapes and sizes; due to this, there will be an advantage to design AuNPs that can perfectly fit into the receptor site.²⁵⁷ A size of 50 nm demonstrates the higher cellular uptake, whereas a size of 20 nm or less shows the excellent tumor penetration.²⁵⁸ NPs in the size of 23 nm improved in the cellular uptake than the size of 85 nm for silica dye–doped NPs.²⁵⁹

Using NPs in the medical sciences would result in improved therapeutic efficacy, easier drug administration, fewer unwanted side effects, lower systemic doses, and enhanced patient quality of life and compliance.²⁶¹ To explore the NPs in clinical research, further research is required to help in the understanding of the interaction between the NPs and biological systems.²⁶²

The surface properties of NPs are critical for their behavior in in vivo and must be carefully considered in the design and development of NPs for in vivo applications.²⁶³ The surface of NPs can have a significant effect on their behavior in the in vivo. Their unique surface properties, such as the surface charge, functional groups, and chemical composition, can affect the interactions of NPs with cells and biomolecules in the biological system.²⁶⁴ The most important aspects of the surface of NPs are the presence of coating or functional groups. These can play a critical role in the targeting and uptake of NPs by cells and can also affect the circulation time and stability of NPs in the biological system.²⁶⁵ For example, the presence of specific targeting molecules such as peptides or antibodies on the surface of NPs can improve their selectivity for specific tissues or cells. Another important aspect of the surface of NPs is the chemical composition, which can affect the toxicity and biocompatibility of the NPs.²⁶⁶ For example, NPs made of biodegradable polymers such as PEG can have a reduced toxicity profile and a longer circulation time in the biological system.²⁶⁷ The surface charge of NPs can also affect their behavior in the in vivo. The presence of negatively charged NPs tends to have a higher degree of stability in biological fluids and can be taken up more efficiently by cells, whereas positively charged NPs can have a greater tendency to aggregate and be rapidly cleared by the reticuloendothelial system (RES).²⁶⁸ NPs can exhibit a variety of behaviors in vivo, depending on their size, shape, composition, and surface properties. Several NPs are taken up by cells and can be used for targeted drug delivery, whereas others are rapidly cleared from the body by the immune system.²⁶⁹ The behavior of NPs can also be influenced by their interactions with biomolecules such as proteins and lipids in the body. The NPs can have different biodistribution patterns, depending on the route of administration, such as oral, topical, or intravenous injection. Some NPs can have specific targets such as cancer cells, and they can also have different ADME and pharmacodynamics. The charge of NPs can have a significant effect on their behavior in vivo.²⁷⁰ Negatively charged NPs tend to have a higher degree of stability in biological fluids and can be taken up more efficiently by cells.²⁷¹ They also tend to interact less with proteins, which can reduce the risk of an immune response. On the other hand, positively charged NPs can have a greater tendency to aggregate and can be rapidly cleared by the RES, which can limit their circulation time in the body.²⁷² The charge of NPs can also affect their biodistribution patterns. Positively charged NPs tend to accumulate in the liver and spleen, whereas negatively charged NPs can have a more widespread distribution throughout the body.²⁷³ Another important factor is the charge density of the NPs, which can directly affect the behavior and stability of the NPs in in vivo. High charge density can improve the stability of the NPs and can also enhance the toxicity along with rapid clearance.²⁷⁴ The charge of NPs is an important consideration in the design and development of NPs for in vivo applications, as it can have a significant impact on biodistribution patterns, their stability, and circulation time.²⁷⁵

8 CURRENT LIMITATIONS

NMs have the potential that can be implemented in cancer diagnostics and therapies.²⁷⁶ However, it is critical to address the opposite side of the coin, specifically, unexpected harmful effects of NMs like cytotoxicity, effect of size on toxicity, retention period, biodistribution, efficacy, and physiological response, which have been widely studied.²⁷⁷ Many of them appear to conflict with one another. The lack of consistent knowledge on NMs could cause delirium and have a severe influence on human health.²⁷⁸ Although the limitations mentioned in general are applicable toward any NP, the following instances are specific to AuNPs. Toxicity: AuNPs toxicity to biological systems has long been a subject of research. Surface chemistry, shape, targeted ligand, size, elasticity, and composition of AuNPs all have an impact on their toxicity.²⁷⁹ Together with the complexity and variability of human cells and tissues creates a challenging situation and makes it difficult to investigate the effect and responses of the biological system to the delivery of AuNPs in a comprehensive manner.²⁸⁰ The toxicity of AuNPs has been linked to their surface charge. It was identified that positively charged particles are more harmful than negative or neutral.

NPs are the basic building blocks for the several important applications in the scientific fields because of their distinct characteristics, such as targeting potential, high surface-to-mass ratio, and capability of adsorbing and transporting additional compounds. This qualifies them for biomedical application.²⁸¹ Application of NMs and innovative nanotechnological development can be a successful potential strategy. NMs improve present technological efficiency, but they can also enhance the amount of water that can be used. On the other hand, NMs will assist in the establishment of technologically advanced and highly efficient treatment facilities.²⁸² This will be helpful to lower the cost of anticancer drugs and medication development. To meet these objectives, NMs need to be produced at a low cost while maintaining large synthesis. Reusability, stability, and workability in industrial applications are other important considerations for their improvement and large-scale production.²⁸³ The toxicity of NMs in vitro and in vivo must be evaluated in both short- and long-term approaches. Despite the fact that nanotechnology is the most recent industrial development, there is certainly a requirement for strong and well standards to be established regarding the application, release, and processing requirements for NMs.⁵

9 CONCLUSION AND FUTURE PERSPECTIVES

The greatest problems in cancer therapy have emerged with the advancement of modern healthcare. The theranostic approach, which is a combination of therapy and diagnosis, is gaining popularity. It has been proposed as a technique for assisting the transition from traditional, nonspecific medicine to modern precision or personalized treatment. Compared with conventional screening modalities, for example, radionuclide and MRI, optical imaging has several distinct benefits that make it a desirable diagnostic tool. Transition metal complexes have recently gotten a lot of focus as a potential substitute to traditional dyes in optical sensors because of their high stokes shifts, extended lives, and simplicity of structural modification. Because of the inherent disadvantages of optical therapy, clinical and preclinical research studies demonstrated that PTT alone is often difficult to destroy malignancies and kill deep-located cancers. To improve PTT's therapeutic benefit while reducing its substantial adverse effects, a new direction combining PTT with other treatment techniques is desired. Due to their unique physicochemical features, two-dimensional TMDCs, as typical ultrathin 2D layer NMs, have recently attracted attention in a variety of sectors, including biomedicine.

Therefore, the development of effective and safe chemotherapeutic agents is important, to strengthen the quality of life, boost the rate of survival, and, most significantly, and extending the lifespan of humans. NM-assisted combination medicines are becoming more prevalent as nanoscience progresses. Metal-based NPs recommended resolving the drug resistance. These NPs interact positively with biomolecules in the cell and can be more effectively used in the development of potential medications for the treatment of cancer. Metallic-based NPs have been suggested to defeat cancer and to increase the effectiveness of healing, diagnosis, photoacoustic imaging, PTT, valuable for prophylactic, antiviral medications, and laser therapy for cancer cells. Because of their antiviral, antibacterial, anti-inflammatory, and antifungal properties, NPs have a lot of potentials to be used as anticancer agents. The molecular mechanisms and relationships that support these kinds of characteristics are not completely explored. The relationships of NMs with cellular and biotic ecological systems, especially in the modification of NPs, are another topic that requires further investigation. Finally, there is an essential need to investigate the toxicological and pharmacokinetics features of metal-based complexes; these NPs are the most innovative and have potential in the area of chemotherapeutics. In this review, the current developments, the recent potential of the plant and metal-based NMs, and current limits are discussed, as well as recommendations for more effective use of NMs in cancer therapy.

AUTHOR CONTRIBUTIONS

Literature review; writing—original draft preparation and figures: Sunil Kumar. Editing: Abhishek Kumar Sharma, Monu Kumar Shukla, and Gururaj K. Jayaprakash. Rajiv K. Review: Tonk and Dinesh K. Chellappan. Conceptualization: Sachin Kumar Singh, Kamal Dua, and Faheem Ahmed. Supervision: Sanjib Bhattacharyya and Deepak Kumar. All authors read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declared no potential conflict of interests with respect to the research, authorship, and/or publication of this article.

ETHICS STATEMENT

Not Applicable.