Harnessing the power of targeted metal nanocarriers mediated photodynamic and photothermal therapy

Abstract

The treatment of cancer has become a profoundly intricate procedure. Traditional treatment methods, including chemotherapy, surgery and radiotherapy, have been utilized, while notable progress has been achieved in recent years. Among targeted therapies for cancer, folic acid (FA) conjugated metal-based nanoparticles (NP) have emerged as an innovative strategy, namely for photodynamic therapy (PDT) and photothermal therapy (PTT). These NP exploit the strong attraction between FA and folate receptors, which are excessively produced in several cancer cells, in order to enable precise administration and improved effectiveness of treatment. During PDT, metal-based NP functionalized with FA are used as photosensitizers which are activated by light, and produce reactive oxygen species that cause cancer cells to undergo apoptosis. Within the framework of PTT, these NP effectively transform light energy into concentrated heat, specifically targeting and destroying tumor cells. This review examines the fundamental mechanisms by which these NP improve the effectiveness of PDT and PTT while simultaneously presenting important findings that demonstrate the effectiveness of FA-functionalized MNP in laboratory and animal models. In addition, the paper also discusses the problems and potential directions for their clinical translation.

Graphical Abstract

1. Introduction

Cancer, a highly malignant and lethal ailment, is a prominent concern across the globe due to its escalating prevalence in the 21st century. According to the American Cancer Society (ACS), cancer is considered the second most prevalent cause of mortality in the United States. In the year 2023, there are roughly two million newly identified cases of cancer, resulting in over half a million fatalities [1,2]. Despite notable advancements in the field of cancer therapy, it continues to persist as a prominent cause of mortality globally, even in nations characterized by diverse degrees of public health infrastructure and economic prosperity [3,4]. The conventional methods of combating cancer, including surgical intervention, chemotherapy, radiotherapy and combinational therapy, are associated with significant undesirable consequences on healthy cells and tissues, which can have a detrimental influence on the overall well-being and quality of life of individuals [5,6]. In recent times, there has been growing promise in the utilization of phototherapy-based approaches, either independently or in conjunction with established standard medicines, as a means to reduce the likelihood of cancer development or mortality [7].

Phototherapy is a therapeutic modality employed in the medical field, wherein light is utilized for the treatment of many ailments, including malignancies and peripheral infections [8,9]. Its primary objective is to restore physiological equilibrium inside the body and alleviate symptoms of depression. Presently, two distinct forms of phototherapy, namely photothermal therapy (PTT) and photodynamic therapy (PDT), have been employed in the treatment of various disorders [10]. Nanomaterials have been increasingly employed in several facets of cancer management within the field of nanomedicine in recent times [11]. Metal nanoparticles (NP) have garnered significant interest over the past decade owing to their distinctive physical characteristics which are currently being used for PDT as well as PTT. However, non-selective of metal NP may reduce its therapeutic potential, therefore, requires conjugation with various active ligands such as folic acid (FA), hyaluronic acid (HA) and arginyl-glycyl-aspartic acid (RGD) [12].

The folate receptor (FR) is a receptor found on the cell’s surface that serves as a biomarker for cancer owing to its abundance of residues containing cysteine [13]. FR exhibits heightened expression levels in cancerous epithelial cells, hence enabling the distinction between these cells and their normal counterparts [14]. FA is a preferred agent for preferentially attaching to FR with an impressive affinity for binding (Kd˜1010 M) [15,16]. FA and its conjugates exhibit preferential internalization by cancerous cells that excessively express FR through a mechanism known as receptor-mediated endocytosis [17]. However, there are many other targeting ligands such as HA and RGD can be used to functionalized metal NP, but FA offers several advantages over these ligands in terms of targeting specificity, cellular uptake, biocompatibility and stability and versatility in functionalization (Table 1). This review primarily concentrates on the various formulations of metal nanocarriers that are appropriate for PTT and PDT of cancer, with a specific emphasis on those targeted to the FR (Figure 1).

Table 1.

Comparison of various targeting ligands in metal nanoparticles.

Characteristic feature	Folic acid (FA)	Hyaluronic acid (HA)	Arginyl-glycyl-aspartic acid (RGD)	Ref.
Targeting specificity	Targets FR which are overexpressed in cancer cell, thus results in high specificity	Less selective than FA because it targets CD44 receptors, which are present on a wide variety of cells including cancer cells	Targets αvβ3 integrins present on both cancerous and non-cancerous cell, resulting in broader but less specific targeting	[18–20]
Cellular uptake	Receptor-mediated endocytosis, leading to efficient internalization of nanoparticles by cancer cells	CD44-mediated endocytosis, which is effective but not as specific or efficient as folate receptor-mediated uptake	Receptor-mediated endocytosis, but the uptake efficiency can vary depending on the expression level of integrins	[21–23]
Biocompatibility and stability	Excellent biocompatibility and stability in biological environments	Good biocompatibility, but it is susceptible to rapid degradation by hyaluronidase, which can affect the stability	Biocompatible but can be prone to enzymatic degradation, requiring additional modifications to enhance stability	[24–26]
Versatility in functionalization	Can be easily conjugated to various metal nanoparticles using straightforward chemical reactions	Can be conjugated to metal nanoparticles, but the chemical processes are more complex and may require specific conditions to maintain the integrity of HA	Can be conjugated to metal nanoparticles, but the synthesis and conjugation processes are typically more involved and less versatile than those for folic acid	[27–29]

Figure 1.

Graphical abstract of folic acid functionalized metal nanocarriers in photodynamic and photothermal therapy.

1.1. Photothermal therapy

The application of localized heating to malignant cells at a temperature of 70°C, as well as systemic hyperthermia (heating to 41–47°C), has been documented since the beginning of the nineteenth century [30]. In the course of local heating or hyperthermia, cells experience irreparable damage as a result of protein denaturation and cellular membrane breakdown. However, it should be noted that such thermal therapies might also result in harm to normal tissues. in the passage of time, the integration of radiation from lasers with thermal cancer therapy has introduced a novel approach for the targeted treatment of cancer [31,32]. The utilization of laser radiation through fiber-optic waveguides is increasingly being employed in the field of cancer therapy, commonly referred to as laser hyperthermia [33]. One significant limitation associated with laser treatment is the necessity for high-power lasers in order to achieve optimal induction of tumor cell death. Later on, the concept of PTT was introduced, wherein a photothermal agent (PTA) facilitates the targeted application of heat inside a specific local area [34].

PTT is a methodology which converts laser illumination into thermal energy subsequent to its absorption by PTA. The mechanism by which PTT induces cellular damage involves the localized increase in tissue temperature, resulting in hyperthermia. This effect is shown specifically in tissues that have accumulated the PTA and are concurrently subjected to laser irradiation, thereby demonstrating a dual selectivity [35].

1.2. Photodynamic therapy

The fundamental idea that underlies PDT for the treatment of malignancies involves a series of photochemical reactions that are initiated by a photosensitizer (PS) medication upon activation by light [36]. Upon exposure to an appropriate wavelength, the PS medication undergoes irradiation, leading to its activation into the singlet excited state (S1). As a result, through a process of intersystem crossing, it transitions to the triplet state (T1). The duration of the T1 state surpasses the state of S1, hence enabling prolonged interactions between the PS medication and the adjacent molecules in the T1 states [37]. There are two distinct processes, namely Type I and Type II, that have been identified for events occurring at the T1 state. The Type I phenomena encompasses two primary processes: the removal of an atom of hydrogen and electron transfer. These mechanisms manifest inside the stimulated PS and the substrate, which may encompass a solvent/biomolecule or an alternative PS. As a consequence of these interactions, free radicals are formed. The Type II process pertains to the transmission of energy between a PS that has been triggered by light and molecules of oxygen in its ground state, commonly referred to as triplet oxygen (³O₂). The process of transferring energy will lead to the generation of a series of reactive oxygen intermediates (ROI), including singlet oxygen, hydrogen peroxide, superoxides and hydroxyl radical. The ROI, owing to their limited lifespan, promptly interact with essential biomolecules, resulting in the targeted impairment of cancerous cells [38,39]. The degradation of biomolecules is constrained by the dimensions of the diffusing sphere of ROI, specifically in the instance of singlet oxygen (¹O₂) when it is smaller than 0.1 m [40]. Therefore, the precise placement of PS is of utmost importance in order to provide focused and efficient PDT [41].

2. Metal nanocarriers in phototherapy

At present, considerable advancements have been achieved in the field of tumor therapy. Nevertheless, the intricate tumor microenvironment (TME) hinders the immune system’s ability to recognize and respond to cancer cells that have been triggered [42]. The presence of hypoxia in tumor tissue has consistently posed a challenge to the effective implementation of PDT in clinical settings [43]. Additionally, the diminished relative oxygen pressure of TME also diminishes the efficacy of PDT [44]. Metal NP have garnered significant interest over the past decade owing to their distinctive physical characteristics, including plasmon resonance and fluorescence amplification, as well as their improved catalytic behavior, which is of chemical significance [45,46]. Metal-based nanomaterials can be classified into different categories, which includes NP consist of pure forms of metals such as silver, copper, gold, titanium, platinum, zinc, magnesium and iron NP, metal oxide NP, such as titanium dioxide, silver oxide and zinc oxide. Additionally, doped metal, metal oxide and metal nanomaterials are considered. At last, metal sulphide and metal organic frameworks (MOFs) nanomaterials are examined, including AgS, CuS and FeS NP, as well as MOFs based on zinc, copper and manganese [47].

Metal nanocarriers possess a substantial specific surface area and an advantageous area-to-volume ratio, hence manifesting many distinctive physicochemical features that render them valuable in the context of cancer therapy. Metal nanocarriers possess several advantages above NP of different kinds as therapeutic agents, mostly attributed to their intrinsic anticancer activity. This unique characteristic surpasses the prerequisites of alternative carriers for the administration of therapeutic and diagnostic drugs [48]. Moreover, these materials possess biocompatibility and may be readily eliminated from the organism. Simultaneously, it is possible to encapsulate or attach therapeutic agents to metal NP, thereby utilizing the metal NP as carriers for the therapeutic agents. The modification of the metal nanoparticle’s surface with a conjugated targeting moiety enables the selective targeting of cancer cells [49]. Furthermore, the utilization of metal NP in diagnostic and imaging applications is attributed to their inherent features [50,51]. This review is an attempt to understand the utilization of FA functionalized metal nanocarriers in cancer phototherapy. The aforementioned sections below summarize various metal nanocarriers used in phototherapy. Various types of FA functionalized metal NP are elaborated in (Table 2).

Table 2.

Types of targeted metal nanocarriers used in photodynamic therapy and photothermal therapy.

Type of nanocarrier	Targeting motif	Clinical use	Cancer	In vitro	In vivo	Outcomes	Ref.
GNR/Block copolymer	FA	Imaging, PDT, PTT		MCF-7, A549	–	Targeted imaging and synergistic PDT and PPT effects were achieved	[52]
GNR/HSA	FA	Chemotherapy, PTT		HeLa, HTB-26	–	Significant reduction in cancer cell viability was achieved	[53]
Gold/INP	FA	PTT		MCF-7, KB	–	Enhanced apoptosis in cancer cell due to improved photothermal effect	[54]
Gold/SiO2	FA	Chemotherapy, PTT	Breast cancer	MDA-MB-231, MCF-7	–	Enhanced cytotoxicity and apoptosis due to synergistic chemo and photothermal effect was achieved	[55]
Ag NTs	FA	Imaging, PTT	Ovarian cancer	NIH:OV-CAR3	–	Improved therapeutic effect due to enhanced cellular uptake	[56]
Ag ODs	FA	Imaging, PDT, PTT		HeLa, A549	–	Significant reduction in cell viability of FR positive cells was achieved	[57]
AgNP	FA	PTT	Breast cancer	MDA-MB-231	Breast cancer model in Sprague Dawley rats	Improved chemotherapeutic potency along with PTT	[58]
Mn/hydroxyapatite	FA	PTT	Breast cancer	MDA-MB-231	MDA-MB-231 xenografts in female BALB/c naked mice	Improved tumor specific targeting and treatment efficiency was achieved	[59]
Mn/C6/PD	FA	PDT, PTT		MCF-7, NP69, HeLa	MCF-7 xenografts in female BALB/c mice	Higher photothermal conversion efficiency was achieved	[60]
MoS2/Chitosan	FA	Imaging, PDT, PTT	TNBC	MDA-MB-231, HCC38, MCF-7	HCC38 xenografts in NCr nude mice	Higher antitumor efficacy was achieved in deeper tissue tumor	[61]
Zn Nanosheets	FA	Chemotherapy, PTT		MDA-MB-231, HBL-100	Nulliparous swiss albino mice	Minimal in vivo systemic toxicity was achieved	[62]
TiO2/Phthalocyanine	FA	PDT		HeLa, A549	HeLa xenografts in female BALB/c nude mice	Enhanced two photon absorption was achieved	[63]

PDT: Photodynamic therapy; PTT: Photothermal therapy.

2.1. Gold nanocarriers

An effective method to cancer treatment involves the development of a PTT utilizing gold nanoparticles (GNP) and near-infrared (NIR) light for the treatment of malignant tumors [64–66]. For instance, gold nanorods, have garnered a growing amount of attention as a potentially useful PTA for use in a range of therapeutic treatments for cancer [67–73]. The transversal mode and the longitudinal mode are the names given to the two different surface plasmon resonances that can be seen in GNRs [74–77]. The transverse mode exhibits low intensity and is situated nearly wavelength of 520 nm, while the robust longitudinal mode has the potential for adjustment to encompass the visible and NIR range [78,79]. GNRs, functioning as a hyperthermia agent, possess the ability to absorb light within the longitudinal wavelength range. Consequently, they are capable of converting the energy that they absorb into heat, so inducing a rise in the temperature of the environment that surrounds them. This increase in temperature can lead to irreparable damages to tissues [80–83]. Regardless of the considerable promise of phototherapies within the domain of cancer treatment, some problems persist. In the context of PTT, a notable challenge has arisen in the immediate transformation of light energy into heat energy due to inadvertent harm inflicted on healthy tissues along the laser's trajectory. In the context of PDT, administering treatment through parenteral means presents challenges due to the inadequate water solubility of the PS currently employed, as well as its nonselective distribution to cancerous tumors during therapy [84,85]. Therefore, Choi, et al. [52]; developed glutathione responsive gold nanorods conjugated with FA-PEG block copolymer (FP) and pheophorbide a (PheA) (Figure 2). A gold nanorod (GNR) having 3.84 aspect ratio and plasmon resonance of 873 nm longitudinally, specifically the PheA-grafted GNR100, was synthesized by manipulating the ratio of feed content and the correlation among the absorption band and aspect ratio. This exclusive GNR demonstrated exceptional potential in generating singlet oxygen, photothermal conversion impact and controlled release of PheA mediated by GSH. In the course of examining the dark toxicity and phototherapeutic effectiveness of PheA grafted GNR nanocarriers in the MCF7 and A549 cancer cell lines, it was observed that PDT exhibited an augmented impact specifically in the MCF7 cells. This enhancement can be attributed to the existence of FR on the cellular surface, which facilitated a more efficient internalization of PheA-grafted GNR nanocarriers. The cell viabilities of MCF7 cells revealed a steady reduction as the laser irradiation period increased, while the A549 cell lines demonstrated better cell viability attributed to the absence of FR expression. Their research successfully showed the potential for precise targeting and enhanced phototoxicity toward cancer cells using FA/FP and PheA grafted GNR nanocarriers. This was achieved by incorporating FA as a targeting ligand on GNR surface [52].

Figure 2.

Schematic representation that showcases the application of photothermal enhancement in photodynamic therapy using PheA with glutathione-responsive gold nanorods.

Reproduced with permission from [52]. Copyright 2020 Elsevier.

The integration of functional and structural nanocomponents inside hybrid NP holds the potential to enhance treatment outcomes and improve the overall well-being of individuals affected with diseases, including cancer. Hybrid NP provides the ability to preserve the advantageous characteristics of two distinct types of nanomaterials. Additionally, they enable the deliberate adjustment of their characteristics in an orderly way by integrating functional components [86]. In a study Basurto, et al. [53]; reported the fabrication of FA grafted gold nanorods coated with human serum albumin doxorubicin (HSA-GNR-DX NP) for simultaneous photochemotherapy. NP were generated by a coacervation/desolvation technique, which facilitated an increase in the temperature of solution upon NIR light exposure of around 16.0 ± 1.2 °C. This temperature augmentation could be directly attributed to the photothermal capability of the NP. Furthermore, the assessment of cell viabilities revealed that the incorporation of FA into the NP resulted in increased levels of cellular uptake and thus, higher toxicities. This effect was particularly pronounced in HeLa cells, which exhibited a significant overexpression of FR on their cell surfaces. The application of NIR light irradiation further increased the cytotoxicity of GNR-DX-HSA-FA. Considering the specified experimental conditions, the combined application of chemotherapy and phototherapy resulted in cell death rates of more than 95% for HeLa cells. In comparison, GNR-DX-HSA-FA and GNR-DX-HSA NP achieved viability in cells of approximately 20 and 70%, respectively, without the use of NIR illumination. Hence, the utilization of a combined treatment strategy could be particularly intriguing when dealing with drug-resistant cells, as the application of heat may potentially enhance cell death in an auxiliary or supplementary manner. Moreover, the functionalization of NP with extremely precise ligands has the potential to enhance the delivery of various drugs, thereby enhancing their efficacy and minimizing adverse effects. Additionally, the co-encapsulation of gold nanorods with upconverting NP can be employed for specific treatments and imaging applications, with the aim of minimizing harm to normal tissue [53].

In practical applications, the utilization of high laser strengths is deemed unsuitable for clinical interventions targeting malignancies due to the skin’s limited tolerance threshold. The variation in penetration depths among different lasers is a significant factor of concern in the context of PTT for cancer. The precise control of lasers and PS chemicals is crucial in PTT. The tissue penetration depths of ultraviolet and visible lasers are limited, necessitating the development of new agents that can absorb NIR lasers within the biological window. This is crucial for effectively treating cancers located deep within the body [87,88]. Hence, Gaznavi and colleagues [54] synthesized a nanocomplex consisting of a gold-iron oxide core-shell structure (FA–PEG–G@INPs), coated with polyethylene glycol (PEG) and linked with FA for PTT in cancer. After an investigation into the in vitro effects of photothermal treatment using a synthesized nanocomplex, the survival of KB or MCF-7 cells was shown to exhibit minimal changes following an 808 nm laser treatment. This conclusion was drawn based on the data obtained from the MTT assay and flow cytometry analysis. The observation suggested that the use of NIR laser irradiation alone, without the presence of any PS, did not result in significant cellular death. The primary pathways responsible for cell death resulting from nano-photothermal therapy were further clarified to be mostly associated with apoptosis. Furthermore, it has been proven that the attachment of FA to the nanocomplex enhances the effectiveness of the PTT approach [54].

Low level laser treatment is well recognized secure form of phototherapy that specifically targets tumor tissue and cells [89–93]. Agabeigi, et al.; developed methotrexate loaded gold-silica NP which were conjugated with folic acid (FA-MT/G@SiO₂) in order to target cancer cell for efficient chemo and phototherapy. The utilization of intracellular PTA has been shown to enhance the efficacy of photothermal cancer therapy. There is a prevailing belief that the internalization of photothermal elements by cells is a required phenomenon. After conducting an examination of the intracellular internalization of FA-MT/G@SiO₂ in MCF7 cells and MDA-MB-231 cells, the findings revealed a greater level of fluorescence intensity in MDA-MB-231 cells when targeted NP were employed, as compared with the fluorescence level observed in MCF-7 cells. The increased fluorescence seen in MDA-MB-231 cells can be attributable to enhanced cellular internalization resulting from receptor-mediated endocytosis, which is specifically caused by the overexpression of FR on these cells. Furthermore, the application of G@SiO₂ NP or laser radiation individually did not result in noticeable cell death. However, when FA-MT/G@SiO₂ NP were combined with laser irradiation, a major decrease in the viability of cells was seen in both MCF7 and MDA-MB-231 cells. This indicates that the use of NP, particularly with a targeting approach, can greatly enhance the effectiveness of laser treatments in destroying breast cancer cells [55].

2.2. Silver nanocarriers

Silver nanoparticles (AgNP) are highly notable within the category of metallic nanomaterials, mostly due to their extensive array of uses. Due to their distinctive physicochemical characteristics encompassing optical, thermal and electrical conductivity, they show their efficacy against bacteria, fungi and even viruses [94–96]. Recently, there has been a growing curiosity in the application of AgNP in the field of nanomedicine. This interest stems from the findings of many research entities, who have shown that AgNP possess the ability to elicit antitumoral benefits in both in vitro and in vivo tumor models. Such effects have the potential to enhance a range of oncotherapy strategies and diagnostic techniques [97]. Various researchers have explored the antitumor potential of silver nanocarriers with phototherapy.

Farcau, et al.; [56] devised a novel approach including the development of FA-modified, surface-enhanced Raman scattering (SERS) labeled silver nanotriangles (pATP-labeled ChAgNTs) using para-aminothiophenol (pATP) raman reporter molecule which were biocompatilized by chitosan (Ch). This innovative technique aimed to enable multimodal diagnosis and PTT with targeting ability specifically on human ovarian cancer cells. Metallic NP, commonly composed of gold (Au) or silver (Ag), exhibit a strong light scattering at wavelengths corresponding to their localised plasmon resonance. These NP do not undergo photobleaching and exhibit far higher brightness compared with chemical fluorophores. Indeed, the scattering strengths have a magnitude significant enough to be perceptible to the unassisted human visual system or quantified using uncomplicated light-detection instruments. Due to the numerous advantages, they offer, metallic NP have emerged as a highly regarded option for conducting multidimensional biomedical imaging of living organisms, including cellular structures. This is because these NP offer a number of distinct advantages. Through the application of dark field microscopy, it becomes possible to ascertain the precise localization of NP. Additionally, this technique enables the quantification of their uptake and facilitates the differentiation between distinct modes of particle uptake, such as passive uptake and receptor-mediated uptake. The findings of the cellular uptake investigation demonstrated that targeted NP exhibited a greater degree of uptake and internalization inside cell lines that expressed the FR, in comparison to non targeted NP. This observation was made based on the analysis of microscopic pictures. In addition, it was discovered that the plasmon characteristics of particles are substantially retained in biological environments, which was demonstrated by the fact that the ability to quantify the amount of scattering frequency of the particles can be achieved through measurements conducted within the cells. Because of a rise in the refractive index, scientists were able to detect a red shift in the scattering band of particles found inside cells in comparison to the extinction band of particles found in the cellular medium. The efficacy of targeted PTT for cancer cells was proven through the exposure of cells loaded with NP to a continuous wave Ti:sapphire laser operating at a wavelength of 800 nm. The results revealed a clear correlation between the concentration of NP and the mortality rate of the cells. The utilization of FA pATP-labeled ChAgNTs, which possess several capabilities including dark field bioimaging, SERS recognition and tailored plasmon hyperthermia, presents a viable option for the field of personalized medicine [56].

In recent times, colloidal quantum dots (QDs) have emerged as a focal point in nanomaterial research pertaining to bioimaging, biolabeling and drug delivery. This is primarily attributed to their distinctive characteristics, such as short emission regions, adjustable size, fluorescent robustness, exceptional photostability and a substantial surface-to-volume ratio [98,99]. In the most recent information available, there is evidence suggesting that Ag₂S quantum dots (Ag₂S QDs) generating NIR light have demonstrated efficacy as both imaging and treatment agents [100–102]. Ag₂S QDs are more desirable compared with numerous currently available QDs due to their lack of toxic heavy metals as well as low value of solubility constant (Ksp = 6.3 × 10−50). These characteristics make them extremely biocompatible. Moreover, these entities possess the capacity to assimilate light within the visible/NIR range, specifically between 700 and 900 nanometers. They also have the capability to emit light inside the diagnostic scanning window. Furthermore, they can be fabricated in aqueous environments, incorporating various active compounds [103–105]. Hence, Celikbas and colleagues [57] developed a novel formulation consisting of brominated hemicyanine loaded FA grafted, GSH-coated Ag₂S QDs (Ag₂S-GSH QDs). This formulation was designed to improve phototoxicity through a combination of photodynamic and moderate photothermal effects. The study focused on evaluating the efficacy of these Ag₂S-GSH QDs in FR-positive cancer cell lines, using clinically pertinent 640 nm radiation treatment. The outcomes of in vitro cytotoxicity investigations on HeLa cells expressing the FR and A549 cells lacking the receptor revealed that Ag₂S-GSH-FA/Hem-Br exhibited greater damage on FR-positive HeLa cells in contrast to plain Hem-Br and AS-GSH-FA QDs. This improved phototoxicity can be attributed to the greater absorption of the photosensitive agent via active targeting and combined treatment. Notably, this effect is particularly evident when the agents are administered at a safe dosage level. After being exposed to a laser with a wavelength of 640 nm and a power of 300 mW, resulting in an intensity of 0.78 W/cm2, the survival rate of HeLa cells was significantly reduced after treatment with plain Hem-Br, Ag₂S-GSH-FA, and Ag₂S-GSH-FA/Hem-Br, respectively. In general, the utilization of Ag₂S-GSH-FA/Hem-Br demonstrates the potential for image-guided improved PDT and PTT, making it a viable option for various FR(+) tumors [57].

In a different investigation, Bose, et al. reported the fabrication of FA functionalized quercetin loaded silver nanoparticles (FA@QCT/AgNP) for breast cancer cells. Extensive research in both laboratory and animal settings showed their usefulness in alleviating breast cancer symptoms by facilitating the localised release of QCT at the tumor site and stimulating hyperthermia in response to NIR laser light, which led to the selective destruction of cancer cells. After entering the cells, FA@QCT/AgNP enhanced their chemotherapeutic effectiveness through photothermal efficacy, which in turn enabled apoptosis and inhibited tumor growth [58].

2.3. Iron nanocarriers

Nanocarriers that include multifunctional NP for the purpose of targeting cancerous cells are increasingly being recognized as highly interesting frameworks for both cancer detection and treatment. The development and formulation of nanocarriers have garnered significant interest from scientists [106–108]. Multiple varieties of magnetic particles possess the capacity to convert light energy into thermal energy. Magnetic ternary chalcogenide nanostructures, have been utilized as photothermal transducers [109]. Nevertheless, iron oxide nanoparticles (IONs) have emerged as a noteworthy candidate for PTT due to their unique properties of possessing both magnetic and NIR absorption functionalities. IONs exhibit considerable promise for utilization in biological contexts due to their biocompatible nature, ability to degrade naturally, straightforward production process, and convenient customization for particular use [110]. Furthermore, it should be noted that IONs have received approval for their application as contrast agents in magnetic resonance imaging (MRI) for human subjects. The aforementioned characteristics, together with the extensive recognition of their non-toxic nature, render IONs a promising contender for utilization in cancer therapies by various means such as medication administration, magnetic hyperthermia, PDT and photothermal ablation [111]. The utilization of an external alternating magnetic field (AMF) on ions results in the generation of thermal energy. The consideration of this kind of impact arises while examining the utilization of ionic species as mediators in the context of hyperthermia caused by magnetic fields [112]. At elevated AMF frequency ranges, the thermal energy released by the ions is sufficient to induce temperatures beyond 42°C. Elevated temperatures over 42.8°C induce modifications in numerous cellular structuresh and functions of proteins, ultimately leading to a process of necrosis [113]. Various investigations have been conducted by researchers on IONs as a potential candidate for PDT and PTT.

In a study, for the purpose of conducting targeted PTT, Patel, et al. [114]; synthesized FA coupled, Fe₃O₄-ZnO hybrid NP (Figure 3). Investigations on the photodegradation of methylene blue showed dramatically increased photophysical characteristics of the generated nano-PSs. This was owing to the recombination of charged particles that occurred as a result of ion entrapment by the dissolving Fe3+. When human epithelial colorectal adenocarcinoma (Caco-2) cells were exposed to nano-PSs in darkness, a time- and dose-dependent toxicity was detected. This toxicity was connected with the nano-PSs. The engineered nano-PSs were subjected to ultraviolet (UV) light, which caused a substantial photo-killing impact, leading to a dramatic decrease in the Caco-2 survival rate to as low as 6%. When the impact of irradiation alone was removed from the cells, it was shown that interactions between cells with light-irradiated PSs were the primary cause of the decrease in viability that resulted from treatment. The photo-killing impact was exacerbated even more by the conjugation of FA [114].

Figure 3.

Schematic representation of the photo-induced mechanism of cell death caused by iron oxide-zinc oxide core shell nanoparticles coupled with folic acid, under the influence of ultraviolet (UV) irradiation.

Reproduced with permission from [114]. Copyright 2016 Elsevier.

2.4. Manganese nanocarriers

Manganese (Mn), being the third most prevalent transition metal on the planet, may be synthesized to a diverse range of nanostructures via multiple nanotechnologies [115]. These include NP, nanorods, nanotubes, nanofibers, and other complex structures. In this regard, it is worth noting that Mn-NP can be classified into two primary types, namely Mn oxide NP and Mn-doped NP. It is important to acknowledge that the preparation procedures for these NP are not universally applicable, owing to the need for modification and the intricate nature of their topologies. According to Fu, et al. [116]; it has been proposed that Mn²⁺ has the potential to undergo a transformation into Mn(OH)₂ when exposed to hydrogen peroxide (H₂O₂₎ in a neutral setting. Furthermore, it has been seen in previous investigations on Mn²⁺ that the unstable Mn(OH)₂ compound can be further oxidized by H₂O₂, resulting in the formation of MnO₂. The process of catalytically decomposing H₂O₂ to generate oxygen and concurrently reducing it to Mn²⁺ can be significantly facilitated by the presence of MnO₂ [116]. The subsequent reactions illustrate the complete procedure.

$$\begin{array}{c}{\text{Mn}}^{2+}+2{\text{H}}_2{\text{O}}_2\to \text{Mn}{\text{(OH)}}_2+2{\text{H}}^{+}\\ \text{Mn}{\text{(OH)}}_2+{\text{H}}_2{\text{O}}_2\to {\text{MnO}}_2+2{\text{H}}_2\text{O}\\ {\text{MnO}}_2+{\text{H}}_2{\text{O}}_2+2{\text{H}}^{+}\to {\text{Mn}}^{2+}+2{\text{H}}_2\text{O}+{\text{O}}_2\uparrow \end{array}$$

Park, et al. [59]; introduced a unique nanostructured system that exhibited improved multifaceted capabilities. This system involved the utilization of manganese containing hydroxyapatite (Mn-Hpt) combined with FA and IR-783 fluorescent dye. The objective of the study was to investigate the use of targeted fluorescence imaging for the purpose of guiding photothermal/photodynamic treatment. The investigation was focused on assessing the photodynamic effect of the Mn@Hpt/FA-IR783 NP in vitro upon laser irradiation to MDA-MB-231 cells, and the results were observed using confocal laser scanning microscopy (CLSM). The findings indicated that the cells produced green fluorescence, which can be attributed to the production of singlet oxygen (O₂). This outcome served as the confirmation of synthesized Mn@Hpt/FA-IR-783 NP’ effectiveness in PDT. Furthermore, the results obtained from experiments conducted in BALB/c mice were consistent with the outcomes observed in in vitro settings. Specifically, it was observed that PTT using laser alone was not effective. However, when PTT was performed in the presence of Mn-Hpt/FA-IR-783 NP, the body temperature of the mice increased from 30.6 to 55.2°C [59].

In a study conducted by Zeng, et al. [60]; a versatile nanoplatform was developed. This nanoplatform was composed of hollow mesoporous MnO₂ NP that encapsulated the photosensitizer chlorin e6 (C6). Additionally, the NP were subsequently covered with FA-functionalized polydopamine (PD), resulting in the formation of MnO₂@C6@PD-FA NP. The nanoplatform exhibited the capacity for tumor-targeting, pH-responsive behavior, and oxygen generation, enabling the successful eradication of tumors through a combination of oxygen release and thermal accumulation via PTT and PDT. The nanoplatform, which was biocompatible, biodegradable, and physiologically stable, effectively localized to the tumor site owing to the EPR effect, as well as active targeting by folate. Moreover, these nanoplatform exhibited targeted release of C6 in response to endogenous stimulus such as H⁺ and/or H₂O₂ in the TME, as well as external stimuli like laser irradiation. H₂O₂ can be utilized to generate O₂ and facilitate the release of C6, therefore concomitantly mitigating the toxicity of C6 toward healthy tissue. Moreover, the generated O₂ alleviated the condition of hypoxia within the tumor, thereby significantly augmenting the PDT efficacy subsequent to exposure to a 660 nm laser. In the context of PTT, it has been observed that multifunctional core-shell MnO₂@C6@PD-FA NP demonstrated a superior photothermal conversion efficiency compared with individual NP such as manganese dioxide (MnO₂) NPs or polydopamine-coated silica nanoparticles (SiO₂@PDA NPs). This enhanced efficiency is particularly evident when these MnO₂@C6@PD-FA NP were irradiated with an 808 nm laser, indicating a different thermal-cumulative impact. The efficacy of the combination oxygen-elevating and thermal-cumulative PDT and PTT using MnO₂@C6@PD-FA NP was proven through in vitro as well as in vivo tests. The findings indicated that this combined therapy exhibited superior anticancer efficiency compared with either PTT or PDT used alone. When considering the collective impact, the multifunctional core-shell nanoparticle system demonstrated significant potential as a nanoplatform for the treatment of cancer. In particular, the PD shell underwent depolymerization in the presence of acidic conditions, thereby exposing the MnO₂ core to facilitate subsequent reactions [60].

2.5. Molybdenum nanocarriers

Molybdenum (Mo) is a micronutrient which is vital for human existence. A number of enzymes that contain molybdenum, such as aldehyde oxidase, xanthine oxidase, and sulphite oxidase, play significant roles in many metabolic processes within the human body. Extensive research has been conducted on molybdenum-based nanomaterials (Mo-NMs) in various biomedical applications, particularly in the field of PTT [117,118]. These nanomaterials, such as molybdenum dichalcogenides, molybdenum oxides, molybdenum-based polyoxometalates, and molybdenum-based nanocomposites, possess distinctive chemical and physical properties, along with remarkable biocompatibility and biodegradability [119]. PTT has garnered significant interest in cancer treatment over the past several decades. This is mostly due to its ability to accomplish therapeutic benefits via conversion of NIR light energy into thermal energy, which is then utilised to activate localised and trigger therapeutic effects [119].

In a study, Han, et al. [61]; successfully manufactured upconversion nanoparticles (UCNP) that were grafted onto single-layer MoS₂ nanosheets. These nanosheets were specifically designed for the purpose of NIR fluorescence imaging-guided cancer phototherapy of deeper tissues. The targeting selectivity of this nanosystems has been effectively enhanced in cancerous cells that express FR with the addition of FA decoration. The results from the cytotoxicity studies demonstrated remarkable biocompatibility and little toxicity of these nanosystems. The distinct emission of UCL (upconversion luminescence) from UCNP presents a compelling approach for cellular imaging and tracking, with potential applications in cancer therapy along with imaging. When comparing the efficacy of conventional treatment using only PDT or PTT to the combined treatment, it was shown that the combined approach exhibited a synergistic impact. This effect led to increases therapeutic effectiveness for both in vitro and in vivo cancer treatment. Specifically, the utilization of this nanostructure in NIR-triggered PDT holds promise for enhancing the efficacy of tumor therapy in deep tissue regions. In summary, the findings of this investigation demonstrate the efficacy of the created nanostructure in facilitating bimodal tumor imaging and therapy. These results suggest that this nanostructure has significant potential as a novel theranostic agent [61].

In a separate investigation, Wang, et al. [120]; conducted the synthesis of stable mesoporous silica nanoparticles (MSN) that were integrated with MoS₂ and AIE (Aggregation-Induced Emission) for the purpose of targeted fluorescence imaging and PTT of cancer cells. The PT stability and remarkable PT conversion efficiency of composites were also verified. Moreover, the absorption properties were found to be comparable with the anticipated results. The PhENH₂-MoS₂-FA MS demonstrated rapid cellular uptake in MDA-MB-231 cells, resulting in intense red fluorescence within the cells. In addition, the MDA-MB-231 cells were efficiently eliminated owing to the remarkable PT action of PhENH₂-MoS₂-FA MS upon exposure to 808 nm laser irradiation. This article presents a straightforward approach for the synthesis of fluorescent mesoporous silica nanoparticles. These NP were capable of incorporating different photothermal therapeutic agents, making them an effective tool for biomedical fluorescence imaging and possible cancer therapy [120].

2.6. Zinc nanocarriers

The majority of the currently available PS are classified as members of the porphyrin group. These PS demonstrate a distinctive absorption spectrum, characterised by a prominent peak at around 400 nm, commonly referred to as the Soret band [121]. Additionally, they exhibit other weaker absorption bands within the visible range, known as Q-bands. In contrast, the absorption bands necessitating the activation of these bands are inadequately able to permeate biological tissues, so significantly constraining the efficacy of PDT and serving as a notable drawback in the realm of cancer treatment and other related applications [122]. In order to address this challenge, various strategies are being explored to activate PS using NIR light, which has the ability to deeply permeate tissues [123]. One potential approach involves the utilization of NIR excitable PS. However, their synthesis presents challenges due to the requirement that the triplet electronic energy level of the PS must surpass the singular energy level of the molecule of oxygen. On the other hand, the excitation of PS using NIR light can be achieved by employing pulsed NIR light through a phenomenon known as Two-Photon Absorption (TPA) [124–126]. Nevertheless, traditional PSs generally have a poor two-photon absorption (TPA) cross-section, which imposes limitations on the effectiveness of this method. Numerous endeavours have been undertaken in order to enhance the excitability of TPA by altering the chemical composition of PS or by conjugating them with other chromophores possessing a substantial TPA cross-section. However, such adjustments may lead to intricate and difficult to anticipate alterations in the pharmacokinetics of PDT medications [127].

Kachynski, et al. [128]; proposed an innovative approach that utilized complex optical interactions among incident NIR irradiations from laser and the cellular constituents of specific tumors. This technique resulted in an emission of visible light through a process known as four-wave mixing, which included the production of coherent anti-Stokes Raman scattering (CARS) by the inherent elements of the cell and the second harmonic generation (SHG) by collagen [128]. The CARS and SHG signals were adjusted to align with the one-photon absorption (OPA) band of the PSs, resulting in a notably enhanced effectiveness of PDT in contrast to what achieved using TPA [128]. Nevertheless, this methodology relies on the presence of two synchronized ultrashort pulses in order to induce mixing of four-wave. Furthermore, the process of SHG relies upon the existence of collagen of fibrillar type I, which is the predominant biological substance responsible for generating SHG signals due to its significant 2nd order optical nonlinearity. The amount of fibrillar collagen in tumors exhibits variation, suggesting that there are corresponding variances in the outcome of PDT [129].

Thus, Gu, et al. [130]; proposed an additional nanophotonic idea to achieve effective activation of PSs using upconverted NIR light. This study employs the utilization of tumor targeting and biocompatible zinc oxide nanoparticles (ZnO NP) to facilitate the in-situ conversion of NIR to visible light via the SHG method. In result PSs initiated PDT by absorbing visible illumination. One notable benefit is that emission of SHG can be accurately tailored to align with the peak OPA of any PS by adjusting its wavelength of excitation accordingly. The 2nd order nonlinearity of ZnO NP had a significantly larger magnitude compared with the SHG generating biological medium. Through the utilization of both theoretical modelling and actual observations, the research team demonstrated that the presence of SH illumination, which was produced within ZnO nanocrystals, played a substantial role in the activation of PS. This activation then leads to cell death via initiation of apoptotic and necrotic paths within the cytoplasm. The phenomenon occurred via activation of a PDT drug, Chlorin e6, at the subcellular level. This activation occurred when the drug was excited within its highly absorbent Soret band by SH light. The SH illumination, produced at a wavelength of 409 nm by ZnO nanocrystals, was specifically targeted to cancerous cells and internalized by means of the process of folate-receptor mediated endocytosis. The commencement of PDT utilizing upconverted light resulted in a comprehensive decrease in the intracellular levels of macromolecules. This reduction is believed to be caused by the inhibition of protein and lipid synthesis, indicated cell death caused by PDT in real-time. In potential applications, the utilization of in-situ photon upconversion could be expanded by employing ZnO nanocrystals that are surface-functionalized using a precise organelle targeting group. This strategy offers a robust method for identifying and optimizing the cell's response to phototherapy, which can be specifically launched within a particular cell organelle [130].

Breast cancer is the primary contributor to mortality among women on a global scale. Despite significant progress in the field of detection, a considerable number of women afflicted with breast cancer still succumb to this malignant disease. Despite the fact that there have been advancements in the field of early diagnosis and treatment, resulting in a reduction in the overall mortality rate. Nevertheless, the current therapeutic approaches for aggressive breast cancer in clinical settings exhibit limited efficacy and frequently lead to poor patient adherence due to their low efficacy as therapies and significant systemic negative consequences. To address these difficulties, Vimala, et al. [62]; devised a unique multifaceted drug delivery methods that integrates chemo-PT targeted therapy for breast cancer. The research team effectively generated and characterized a novel nanomaterial known as FA-conjugated PEG coated Zinc Oxide nanosheet loaded with doxorubicin (DX@FA-PEG-ZnO NS) (Figure 4). This nanomaterial exhibited thermally stimulative qualities, pH responsiveness, and sustained drug release capabilities. The DX@FA-ZnO NS, as prepared, exhibited a greater concentration ratio of the anticancer drug. Cellular uptake investigations verified greater absorption characteristics and successful internalization of the DX-FA-ZnO NS in tumor cells. Furthermore, when subjected to NIR irradiation, the FA-DX-ZnO NS demonstrated superior cytotoxicity toward breast cancer cells in contrast to other cells receiving treatment and the control group. This indicates the effectiveness of the chemo-PT targeted therapy. Biocompatibility of FA-DX-ZnO NS when evaluated in vivo, demonstrated little to no cytotoxicity on the bloodstream. The potential for a beneficial interaction between FA-ZnO NS and the pH-triggered release feature of DX in cancerous cells through targeted drug delivery could be a significant factor contributing to a potent therapeutic response. In light of these findings, the newly discovered FA-DX-ZnO NS family demonstrates promise as a drug delivery system capable of targeting tumors and effectively releasing drugs and warmth to tumor cells. This system holds the possibility to facilitate a combined approach of chemotherapy and PTT specifically tailored for cancer treatment. One potential strategy to enhance the effectiveness of cancer treatment and mitigate medication resistance is to employ an efficient approach. In addition to the nano chemotherapeutic aspect of DX@FA-ZnO NS, future investigations may focus on demonstrating its potential application and exploring its utility in diagnostic and remedial imaging. Therefore, it can be inferred that DX@FA-ZnO nanosheets have promise as a viable substrate for numerous biomedical uses [62].

Figure 4.

The synthesis of DX-FA-ZnO NS as a functional drug delivery system for combined chemo-photothermal targeted therapy of breast carcinoma.

Reproduced with permission from [62]. Copyright 2016 Elsevier.

2.7. Titanium nanocarriers

Titanium is one of the most abundantly occurring elements in nature, commonly found in its metallic form, titanium tetrachloride (TiCl₄) and titanium dioxide (TiO₂). Studies have demonstrated that mixed polymorphs of TiO₂ are more effective for biological purposes compared with single crystals. TiO₂, are nanocrystalline nanoparticles with a size of 100 nm. These particles have demonstrated excellent photocatalytic properties when combined with ultraviolet (UV) radiation. TiO₂ NP have become prominent in diverse technological domains, including medicine, energy and biosensing. Modern treatment for cancer has increasingly utilized multiple strategies to rapidly attach to cancerous cells in the presence of an acidic microenvironment. In addition, TiO₂ NP have been associated with a significant increase in the conversion of light into heat and the creation of ROS when exposed to laser radiation. This is due to their exceptional capacity to catalyze chemical reactions using light, their impressive ability to interact well with biological systems, their strong resistance to chemical degradation and their low level of toxicity. TiO₂ NP have the ability to release anticancer medicines inside cells through the redox release process. Furthermore, TiO₂ NP can induce the generation of ROS and oxidative byproducts such as lipid peroxidation, resulting in a decrease in cellular antioxidants [131]. Consequently, Robles and colleagues [132] conducted a study in which they synthesised hollow nanospheres (TiO₂NSP– FA–ZnPc) composed of titanium dioxide (TiO₂) and modified them with FA and ZnPc. The purpose of this modification was to enable targeted PDT specifically for glioblastoma cancer. In the course of examining the cytotoxicity of the TiO₂NSP–FA–ZnPc formulations in FR positive MK cells, it was observed that there was a notable decrease in cell viability at a concentration of 500 µg/mL, as determined by the MTT assay. Furthermore, the measurement of ROS formation conducted utilizing DPBF as a chemical probe. DPBF, being a reductant substance, has the ability to react with ¹O₂. When exposed to UV light with a wavelength of 365 nm, the substance exhibits a characteristic UV absorption peak at 415 nm. One way to detect the presence of ROS is by observing the reduction in absorption of (DPBF), which occurs as DPBF reacts with singlet oxygen and decreases in concentration. The rise in radiation duration resulted in a noticeable decrease in DPBF absorption, indicated the effective generation of ¹O₂ in the case of TiO₂NSP– FA–ZnPc. However, this effect was not observed in non targeted formulations [132].

Liang, et al. [63]; conducted a study in which they synthesized functional titanium dioxide nanoparticles (FA@TiO₂-Pcn) that were coupled with phthalocyanine (Pcn) and FA. These NPs were investigated as potential PS for targeted PDT, both in vitro as well as in vivo. The subcellular distribution of FA@TiO₂-Pcn in FR+ cells (HeLa) and FR− (A549 cells) was assessed using laser scanning confocal microscopy. A greater amount of FA@TiO₂-Pcn was seen to be internalized by HeLa cells in contrast to A549 cells. Cells after pre-treatment with FA, the endocytotic process of HeLa cells was reduced to a level comparable to that of A549 cells. The A549 cells exhibited minimal absorption regardless of the pretreatment with FA, so providing additional evidence that FA@TiO₂-Pcn is internalized more efficiently into HeLa cells compared with A549 cells owing to the presence of the FR, which specifically targets tumors. The FA@TiO₂-Pcn composite demonstrated no cytotoxic effects on untreated HeLa and A549 cells when administered at concentrations below 200 μg/ml. A comparison was conducted between the creation of ROS in FA@TiO₂-Pcn and Pcn solutions. The results revealed that the yield of ROS in the FA@TiO₂-Pcn was 4.5-times greater than that of the Pcn solution with a similar concentration. The photokilling phenomenon exhibited significant results when a little dosage of PS, a brief incubation period in an in vitro setting, and a low dosage of irradiation were employed. The FA@TiO₂-Pcn NPs demonstrated significant anticancer efficacy in in vivo studies, utilizing a low dosage of therapeutic medication and minimal light irradiation. Furthermore, the TPACS (two-photon absorption cross section) of FA@TiO₂-Pcn exhibited an increase of roughly 1.7-fold compared with that of Pcn. This suggests that FA@TiO₂-Pcn possesses a high therapeutic efficacy in terms of two-photon excitation. Hence, it is plausible to consider FA@TiO₂-Pcn as a promising PS for augmenting PDT in the treatment of diverse FR+ malignancies in forthcoming research. This is attributed to its remarkable biocompatibility, targeting potential and therapeutic effectiveness in both OPE-PDT and TPE-PDT [63].

3. Conclusion

Phototherapy is a cutting-edge medical treatment that uses light to treat many illnesses, such as cancer and peripheral infections. It includes both PTT and PDT. The primary objective of phototherapy is to reinstate the body’s physiological equilibrium and alleviate symptoms linked to disorders like cancer. Metal nanocarriers are highly promising for these therapies because they possess the unique ability to generate ROS and induce hyperthermia, both of which are crucial for achieving excellent treatment outcomes. Nevertheless, the effectiveness of metal nanocarriers relies heavily on their capacity to be compatible with living organisms, capable of being broken down naturally, and maintaining stability within the body. Precise localization of tumors through the EPR effect is crucial. However, there are substantial limitations such as lack of selectivity and uptake by the RES. Hence, it is crucial to employ active targeting mechanisms in order to achieve accurate localization of these nanocarriers specifically at tumor locations, thereby augmenting the effectiveness of the therapy. This review has emphasized the use of several metal nanocarriers that have been modified with FA to specifically target FRs on cancer cells using phototherapy. Metal NPs possess distinctive properties that reduce the leaching of PS in PDT, have a large capacity for loading PS, boost the passive absorption of PS through the EPR effect, and may be easily functionalized with various ligands, thereby improving the active absorption of PS. Together, these characteristics improve the overall efficacy of PDT for different types of malignancies.

In addition, current research is continuously discovering novel approaches to enhance the effectiveness of PDT, especially when used in conjunction with other treatments like chemotherapy, immunotherapy and targeted therapy. A comprehensive comprehension of the biological mechanisms underpinning PDT establishes a solid basis for the development of sophisticated procedures that improve the effectiveness of combination therapies. Developing NPs capable of targeting the intricate TME and manipulating the microenvironment of malignant cells is essential for enhancing medication delivery and enhancing the overall impact of combined therapies. However, in order to fully utilize the potential of phototherapy in many applications, more research and collaboration between other disciplines is needed. These initiatives will play a crucial role in enhancing the comprehensive PDT therapy approach for cancer, ultimately resulting in more efficient and tailored cancer therapies.

4. Future perspective

The potential of metal nanocarriers in photodynamic and PTT for cancer treatment is intriguing. However, there are various problems that need to be addressed in order to fully exploit their capabilities. A significant obstacle is the attainment of precise targeting to guarantee selective distribution to tumor locations, while minimizing unintended consequences and improving the effectiveness of therapy. Progress in the fields of molecular biology and nanotechnology can facilitate the creation of versatile nanocarriers that have the ability to perform both imaging and therapy simultaneously. This enables the monitoring of treatment response in real-time and provides fine control over therapeutic interventions. Another obstacle that needs to be addressed is the capacity of metal nanocarriers to break down naturally and their ability to remain compatible with biological systems over an extended period of time. It is essential for the clinical application of these nanocarriers that they can be safely broken down or eliminated by the body. Interdisciplinary collaboration among fields such as materials science, oncology and pharmacology will be crucial for the development of nanocarriers that satisfy these safety requirements. Investigating the potential synergies between phototherapy and other new sciences, such as gene therapy, immunotherapy and personalized medicine, offers a promising route for further exploration. The integration of different modalities has the potential to result in more efficient and tailored treatment regimens. By incorporating artificial intelligence and machine learning into treatment planning and optimization, the utilization of nanocarriers can be enhanced, resulting in precise dosing and reduced occurrence of adverse effects. It is necessary to also tackle the regulatory obstacles. Developing uniform procedures for assessing the safety and effectiveness of nanocarriers is crucial for obtaining regulatory authorization and guaranteeing consistent clinical results. To summarise, the prospects for metal nanocarriers in phototherapy are promising. However, it is crucial to address existing obstacles through interdisciplinary research and innovation. By resolving these concerns, we may unleash the complete capabilities of these sophisticated therapies and introduce more efficient cancer treatments into clinical application.

Funding Statement

The authors (N Nasir and S Wahab) extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding them through Large Research Project under grant number RGP2/221/45.

Author contributions

J Chandra, N Nasir, S Wahab, A Sahebkar and P Kesharwani wrote the manuscript. P Kesharwani proofread and supervise it. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.