Nanophotocatalysts are a class of nanomaterials that drive chemical reactions through light activation, typically ranging in size from one to several hundred nanometers. These catalysts function by absorbing photons, exciting internal electrons to higher energy states, and subsequently generating electron–hole pairs. These electron–hole pairs can actively participate in chemical reactions, facilitating the transformation of various reactants regardless of the reactants’ inherent photochemical activity (39–45). Due to their exceptional photoelectric properties, nanophotocatalysts have demonstrated remarkable applicability across various fields. Their applications span from water splitting for hydrogen production and pollutant degradation to photonic energy conversion, catalysis in organic synthesis, and precise medical interventions such as the elimination of cancer cells (46–54). By optimizing reaction conditions, these nanomaterials significantly enhance reaction efficiency, showing tremendous potential in energy production, environmental remediation, and biomedicine. Nanophotocatalytic technology not only fosters advancements in cutting–edge fields but also provides innovative solutions for green and sustainable technologies, illustrating expansive research and application prospects.

As current cancer treatment methods struggle with severe side effects and the challenge of incomplete cures, the scientific community is vigorously exploring novel therapeutic strategies that are faster, more thorough, highly targeted, and safer. Photocatalytic elimination therapy, an emerging approach in cancer treatment, has garnered significant attention from researchers and clinical practitioners due to its mechanism of utilizing photocatalysts under specific light irradiation to generate ROS that directly attack cancer cells. Compared to traditional chemotherapy and radiotherapy, nanophotocatalysts exhibit distinct advantages; these catalysts synergistically combine the excellent optical and physicochemical properties of inorganic materials with the targeted functionalities of biomolecules, thereby enhancing therapeutic efficacy. Moreover, photocatalytic therapy can incorporate multifunctional drug molecules, achieving a synergistic effect that enhances precision and safety in treatment (108, 109). For example, a supramolecular photocatalyst, Nano–SA–TCPP (nanoporphyrin metal–organic framework), was developed by Zhu and colleagues. In an animal model, cancer cells were injected into the right dorsal subcutaneous culture of mice when the tumor volume exceeded ∼100 mm³, and solid tumors were treated with light irradiation at a wavelength of 600–700 nm. Experimental results showed that solid tumors (100 cubic mm³) were eradicated in as little as 10 minutes and the survival rate of mice increased from 0% to 100% within 50 days after treatment (110). Li and his team used ultrathin copper–tetrathione (4–carboxyphenyl) porphyrin (Cu–TCPP) MOF nanosheets to inject tumor–bearing mice, and then photothermal and photocatalytic irradiation was performed with an 808 nm laser and a 660 nm laser. Laser for coordinated photothermal and photocatalytic treatment, which showed that the cancer cells showed malignant cell shrinkage, nuclear condensation and fragmentation, which improved the survival rate of mice. Chen and his team designed and synthesized a gadolinium–porphyrin–based polymer, which was injected into the tail vein of mice and irradiated with a 635 nm laser for 10 minutes, resulting in the killing of more than 90% of the cancer cells (113). Tables 3 – 5 summarize in detail several commonly used photocatalysts for cancer therapy and their characteristics, accompanied by the performance of photocatalytic treatment of tumors in animal experiments, which provide important insights into the advancement of this promising therapeutic modality (111–115, 123–143).

Extensive scientific research has elucidated the biological impacts of the highly efficient photocatalysts previously discussed. For example, studies have demonstrated that nano–TiO₂ particles, once internalized by biological systems, can activate and induce interactions with alveolar macrophages, phagocytes, and microglial cells, leading to the generation of ROS (144). The production of ROS is closely linked to oxidative stress responses within cells, which can compromise membrane integrity and function, potentially triggering inflammation or cellular damage. Additionally, in vivo experiments and oral ingestion of nano–TiO₂ have shown that these particles can enter the bloodstream, potentially affecting liver and kidney function and causing organ damage. Nano–TiO₂ and its aggregates can also enter cells through interactions with surface receptors, and once internalized, they may exert mechanical stress on cell membranes, thereby affecting the stability and activity of membrane–associated receptors and ion channels (145, 146).

However, these findings regarding the toxicity of nano–TiO₂ do not imply uncontrollable risks for humans or the environment. Recent studies have revealed that at lower concentrations, nano–TiO₂ exhibits negligible toxicity (147, 148). With its excellent biocompatibility and superior drug delivery capabilities, nano–TiO₂ has demonstrated significant potential in targeted cancer therapy and tumor treatment. By interacting with cancer cell membranes, nano–TiO₂ effectively induces the production of ROS, such as ·O₂ ^– and ·OH, disrupting cancer cell structures and enhancing the efficacy of cancer therapies (149–152). Moreover, nano–TiO₂ is widely utilized in photothermal therapy (PTT), photodynamic therapy (PDT), and sonodynamic therapy (SDT), where it facilitates precise targeting and control via external stimuli, achieving targeted delivery and treatment of cancer cells (149, 153, 154). Given its low phototoxicity and high biocompatibility, nano–TiO₂ holds great potential in phototherapy applications, demonstrating notable therapeutic effects in preclinical and clinical studies (130, 131).

Similar to nano–TiO₂, nano–In₂O₃ exhibits excellent chemical stability and low toxicity. At ambient temperature and pressure, In₂O₃ is resistant to spontaneous decomposition, significantly reducing its toxicity risk during storage and application. Existing studies suggest that In₂O₃’s acute toxicity is relatively low, and short–term exposure to high doses inflicts minimal harm to biological organisms (155). Furthermore, reports indicate that workers exposed to indium over extended periods have shown no direct health abnormalities linked to indium exposure. Additionally, nano–In₂O₃, when combined with reduced graphene oxide (RGO), exhibits enhanced anticancer activity in colorectal and liver cancer cells while maintaining superior biocompatibility with normal cells (156). Meanwhile, g–C₃N₄, a non–metal semiconductor material composed of carbon and nitrogen, is generally considered to have low toxicity. In cellular experiments, low concentrations of g–C₃N₄ caused minimal morphological changes in cells, suggesting its low toxicity (157). Moreover, systemic administration and intratumoral injection of g–C₃N₄ demonstrated favorable biocompatibility, and when coupled with localized light treatment, it effectively reduced tumor size (158). Research has further categorized WO₃ as a low–toxicity substance, with studies by Samaneh et al. confirming that WO₃–NS does not exhibit significant toxicity even at higher concentrations (159).

In conclusion, nanocomposite materials integrating TiO₂, In₂O₃, and g–C₃N₄ exhibit great potential in the field of photocatalytic cancer therapy. These materials not only enhance photocatalytic performance through the design of composites but also demonstrate excellent biocompatibility and low toxicity, offering promising prospects for future cancer therapies. Researchers have optimized the structures and functionalities of these composites, improving the precision and efficacy of targeted therapies, thereby laying a solid foundation for the practical application of photocatalytic treatments.

The long–term toxicity of nanophotocatalysts is a problem that stems mainly from their bioaccumulation, metabolic impairments, and the potential inflammatory responses that they trigger. These toxic effects may lead to cellular oxidative damage, genetic mutations and increased risk of chronic diseases. In the following, how to solve its long–term toxicity problem is systematically elaborated from the perspectives of inhibition of toxicity accumulation meter, metabolic regulation, and inflammation inhibition.

Discussed from the perspective of inhibiting toxicity accumulation, the accumulation of toxicity can be reduced by designing photocatalytic materials strained. The surface charge and hydrophilicity of nanoparticles significantly affect their distribution and accumulation in biological tissues. It has been shown that surface–coated polyethylene glycol (PEG) or silicon dioxide (SiO₂) can form a spatial site barrier that reduces the interaction of nanoparticles with cell membranes. For example, Mano and his team surface–modified TiO₂ nanoparticles with polyethylene glycol (PEG) to eliminate nanoparticle aggregation. The results showed that modifying TiO₂ with PEG reduced its cytotoxicity and decreased the induction of stress–related genes (160). In addition, by modulating the size of the nanoparticles (>20 nm), the catalytic activity can be maintained while avoiding the systemic toxicity triggered by too small particles (<10 nm) through glomerular filtration or the blood–brain barrier. Park’s team investigated the effects of Ag nanoparticles of different sizes (20, 80, and 113 nm) on cells. Comparisons were made in in vitro assays for cytotoxicity, inflammation, genotoxicity and developmental toxicity. The 20 nm Ag particles were found to have the most pronounced effects on cellular metabolic activity and membrane damage. While larger size Ag nanoparticles had less effect (161).

Discussing from the perspective of metabolic regulation, degradable carrier design can be performed to promote metabolism. That is, the use of biodegradable materials (e.g., chitosan, polylactic acid) as carriers for nanocatalysts can realize the gradual degradation of the materials into non–toxic small molecules that can be excreted via the kidneys or the intestines after completing the catalytic task. In their review, Karlsson and team mentioned that biodegradable polymer nanocarriers hold great promise for enhancing the efficacy and safety of cancer treatments as a drug delivery vehicle. The properties of the polymers can be customized to ensure effective delivery of specific anticancer drugs from small molecule drugs to biologics. Biodegradable polymers can be safely degraded under physiological conditions and are engineered to respond to environmental and external triggers for spatially and temporally controlled delivery through engineering innovations (162).

Discussed from an inflammatory response perspective, the inflammatory response can be slowed by constructing heterojunctions and inhibiting inflammatory signaling pathway activation. The first way is to construct heterojunctions (S–scheme heterojunctions mentioned above) that optimize the efficiency of photogenerated electron–hole separation and reduce nonessential ROS overproduction. Wang and coworkers proposed a new reversible use of semiconductor heterojunctions to modulate ROS levels. The method integrates two metal–based ROS scavengers containing n–type CeO₂ nanoparticles and n–type copper–doped diatom biosilica (Cu–DBs) to form typical n–n semiconductor heterojunctions (Ce/Cu–DBs). Unlike single ROS scavengers or ROS–generating agents that control ROS levels, Ce/Cu–DBs can rapidly eliminate ROS via a cascade catalytic reaction and readily switch to ROS generation via a near–infrared (NIR)–triggered photocatalytic effect. This NIR–mediated ROS modulation system provides a noninvasive strategy for the reversible control of ROS levels in vitro and in vivo to reduce the inflammatory response of the organism (163). The second approach is to inhibit inflammatory signaling pathway activation. Inflammatory responses triggered by nanoparticles are often mediated through the NF–κB or NLRP3 pathways. ZnO nanoparticles with surface–modified polydopamine (PDA) have been found to reduce pro–inflammatory factor release by inhibiting TLR4/MyD88 (Signaling pathway consisting of Toll–like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88)) signaling. After green synthesizing ZnO nanoparticles using Aloe vera extract, Tavakoli’s team used a one–step direct method to surface–modify the nanoparticles with polydopamine (PDA). The results of the study confirmed that the synthesized polydopamine–coated zinc oxide (PDA@ZnO) nanoparticles possess good biocompatibility, have a minimal effect on the inflammatory response of the body, and are not only non–toxic to human cells, but also significantly promote cell survival (164).

In recent years, metal oxide materials such as ZnO, TiO₂, CuO, SiO₂, iron oxides (including Fe₂O₃ and Fe₃O₄), and CeO₂ have garnered significant attention in biomedical applications, particularly in anticancer and antitumor treatments, due to their distinctive physicochemical properties, low production costs, biocompatibility, and potent cytotoxicity (165–167). In one study, Rasha A. and colleagues synthesized Ag–doped WO₃ (3% Ag/WO₃) photocatalysts, which substantially enhanced the photocatalytic efficacy against human cervical cancer cells (HeLa cells). Their results showed that under light irradiation at a concentration of 100 μg/mL for 20 minutes, 3% Ag/WO₃ achieved a 90% elimination rate of HeLa cells, underscoring the role of Ag doping in significantly amplifying anticancer effects (168). Similarly, Gao et al. engineered CeO₂/CuO heterostructures anchored on upconversion nanoparticles (UCNPs), modifying cancer cell membranes to enhance ROS generation. This enabled a synergistic effect between photocatalytic therapy and chemotherapy. In vivo mouse experiments demonstrated that 10 minutes of treatment with CeO₂/CuO–UCNPs under 808 nm near–infrared light resulted in substantial tumor inhibition (100 mm³), with no recurrence observed after 14 days, highlighting the long–term therapeutic potential of this treatment (126).

Mohd Javed and colleagues conducted an investigation into the cytotoxicity of nano–ZnO on various cancer cell types, including human liver cancer (HepG2), human lung adenocarcinoma (A549), human bronchial epithelial cells (BEAS–2B), and rat astrocytes and hepatocytes. Their findings revealed that nano–ZnO effectively induced apoptosis in these cancer cells while sparing normal rat cells. This selective apoptotic induction is believed to be mediated through the tumor suppressor gene pathway, facilitated by ROS generation (169). Tian et al. further demonstrated that nano–ZnO disrupts intracellular Zn homeostasis, leading to lysosomal and mitochondrial damage and inducing ROS production, ultimately resulting in cancer cell death (124, 170). Collectively, these studies provide substantial evidence for the efficacy of photocatalytic technology in the elimination of cancer cells, while showcasing the unique advantages and promising potential of metal oxide–based photocatalysts in advancing cancer treatment strategies.

The mechanism underlying the photocatalytic elimination of cancer cells primarily relies on the chemical reactions initiated by photocatalytic materials under specific light irradiation conditions. The efficiency of the photocatalytic activity of nanophotocatalysts is directly correlated with their ability to eliminate cancer cells. When the energy of photons equals or exceeds the bandgap of the semiconductor material, nanophotocatalysts generate electron–hole pairs under illumination. These electron–hole pairs undergo two key processes. The first and more favorable process involves photo–induced charges participating in redox reactions; holes oxidize H₂O and OH⁻ to form ·OH (see Equation 1), while electrons reduce O₂ to generate ROS, such as ·O₂ ^– (see Equation 2). These ROS induce oxidative stress within the cellular system, which subsequently triggers apoptosis or necrosis in the cells. In contrast, the less desirable second process involves the radiative or non–radiative recombination of electron–hole pairs (see Equation 3), rather than their participation in redox reactions, thereby diminishing the photocatalytic efficiency and weakening the cancer cell elimination capability (38, 72, 168, 171, 172).

To overcome the high recombination rate of the electron–hole pairs, researchers typically enhance photocatalytic performance by combining semiconductor photocatalysts with another suitable semiconductor to form heterojunctions or by doping them with noble metals (e.g., via Schottky junctions) to trap charges, thereby reducing recombination and improving photocatalytic efficiency. These modifications significantly elevate ROS production, thereby inducing more intense oxidative stress responses within cells, ultimately leading to apoptosis or necrosis. Such advancements substantially enhance the ROS generation capacity of nanophotocatalysts, amplifying their potential in cancer cell elimination applications (shown in Figure 2). Figure 3 illustrates the mechanism by which the introduction of S–scheme heterojunctions and OVs elevates the levels of hydroxyl and ·O₂ ^–. This strategy not only improves the degradation capacity of photocatalysts for organophosphorus pesticides but also provides robust scientific evidence and support for their application in the elimination of cancer cells.

Upconversion nanoparticles (UCNPs) are a unique class of nanomaterials characterized by their ability to absorb low–energy photons and emit high–energy photons—a phenomenon known as upconversion luminescence. Under near–infrared (NIR) light excitation, UCNPs emit high–energy visible light, which activates nearby photosensitizer (PS) molecules, resulting in the production of singlet oxygen or ROS that effectively kill cancer cells. Due to the superior tissue penetration of NIR light, UCNPs can facilitate photochemical reactions in deeper tissues compared to traditional visible or ultraviolet (UV) light exposure, thereby enhancing cancer treatment outcomes. In addition to serving as energy donors in photochemical processes, UCNPs can be utilized for NIR light–triggered drug release, imaging, and the activation of therapeutic molecules, achieving more precise cancer therapy (173, 174).

Wang and colleagues developed UCNP–Ce6 complexes by non–covalently binding Ce6 to a polyethylene–glycolated amphiphilic polymer–coated UCNP. After 30 minutes of exposure to 980 nm light at 0.5 W/cm², the UCNP–Ce6 complexes successfully penetrated cancer cells and induced the death of 4T1 breast cancer cells in mice (175). Zhang’s team was the first to demonstrate the application of UCNPs in photodynamic therapy for breast cancer cells (MCF–7/AZ). Following 36 minutes of infrared irradiation, the breast cancer cells exhibited shrinkage and eventually died, showcasing the deep–tissue penetration and high specificity of UCNPs for targeting cancer cells (176, 177). Furthermore, Wang and his team utilized NaYF4 UCNPs co–doped with Yb³⁺ and Tm³⁺, which converted NIR photons into higher–energy photons, activating ZnO nanoparticles and generating a large amount of ROS, thereby significantly enhancing the anticancer effect (178). Gu and colleagues studied a system in which NIR laser radiation, through nonlinear optical interactions with tumor–targeting molecules, induced high–efficiency photocatalysis via single–photon absorption in ZnO, offering improved efficiency over conventional two–photon excitation (174). These studies provide strong evidence for the practical application of phototherapy in cancer treatment, demonstrating the vast potential of UCNPs as an emerging therapeutic modality.

Under ultraviolet (UV) light excitation, TiO₂ nanoparticles exhibit remarkable photocatalytic activity. However, UV light has significant limitations in penetrating biological tissues, with insufficient depth to effectively penetrate deep–seated cancer cells. This limitation hinders the efficacy of TiO₂ nanoparticles in treating deep tumors in vivo. To overcome this drawback, researchers have developed hybrid systems by combining TiO₂ with metals, metal oxides, or carbon nanomaterials to reduce its bandgap energy, thereby enhancing its photocatalytic activity under visible light and expanding the potential applications of photocatalysis in cancer treatment. For instance, incorporating SiO₂ into TiO₂ has been shown to improve its cytotoxicity against cancer cells. This combination broadens the light absorption spectrum and increases the photosensitivity to cancer cells (179). Such enhancements not only extend TiO₂’s application in photodynamic therapy (PDT) but also offer promising therapeutic strategies for targeting cancer cells in deeper tissues.

Moreover, folic acid–conjugated SiO₂–TiO₂ nanoparticles, as a novel photosensitizer, have demonstrated superior active targeting capabilities in cancer treatment. Studies by Nurhidayatullaili et al. indicate that the addition of folic acid significantly inhibits cell proliferation and enhances the targeting of cancer cells. Under UV irradiation at various time points, folic acid–conjugated SiO₂–TiO₂ exhibited increased cytotoxicity against cancer cells. As the concentration of folic acid–conjugated SiO₂–TiO₂ nanocomposites increased, the survival rate of cancer cells notably decreased. In the presence of 12.5 µg/mL of folic acid–conjugated nanocomposites, the cancer cell survival rate dropped from 100% in the control group to 93%, 82%, and 78% at different time intervals, respectively. When the concentration of folic acid–conjugated SiO₂–TiO₂ increased to 100 µg/mL, the survival rate further decreased to 57% (179, 180). These findings not only highlight the potential of folic acid–conjugated SiO₂–TiO₂ in photocatalytic cancer therapy but also offer valuable insights for the future development and application of similar nanocomposites.

Photocatalytic technology relies on generating a substantial amount of ROS to ablate cancer cells. However, this strategy is often hindered by the rapid recombination of the electron–hole pairs within the photocatalyst, limiting its efficacy. To address this limitation, researchers have developed a novel piezoelectric–assisted photocatalytic therapy that effectively enhances the separation of the electron–hole pairs at both bulk and interface levels, thereby triggering an intracellular ROS surge and inducing cancer cell apoptosis (181). Kang et al. employed calcination and liquid exfoliation techniques to synthesize heat–treated natural sphalerite nanosheets (NSH700 NSs), which exhibited remarkable piezoelectric photocatalytic effects. Under 660 nm laser irradiation for 10 minutes, combined with ultrasound stimulation, NSH700 NSs significantly reduced tumor volume (181). This enhanced photocatalytic performance is attributed to efficient charge separation and transfer mechanisms driven by a synergistic effect of polarized electric fields, band bending, and the unique heterojunction structure (182, 183). Compared to conventional photosensitizers, NSH700 NSs demonstrated superior photocatalytic activity, effectively disrupting the redox balance within cancer cells, ultimately leading to apoptosis. Cheng et al. further introduced a novel sonosensitizer, an oxygen–deficient piezoelectric nanocomposite (bismuth–doped oxygen–deficient barium titanate), which enhanced ROS production via sonodynamic therapy (SDT), significantly increasing the rate of tumor cell apoptosis (184–187).

As piezoelectric–assisted photocatalytic therapy continues to evolve, future research will delve deeper into its potential applications in cancer treatment. This innovative therapy not only facilitates direct tumor cell ablation through ROS generation but also synergizes with other mechanisms, such as thermoacoustic effects and enzyme catalysis, to further amplify therapeutic efficacy (188, 189). Looking ahead, piezoelectric photocatalytic materials are expected to achieve higher catalytic activity, improved biocompatibility, and reduced toxicity, offering safer and more effective options for cancer treatment. Additionally, this emerging technology lays a solid experimental foundation for broader biomedical applications, positioning piezoelectric–assisted photocatalytic therapy as a promising frontier in oncological treatment.