Titanium dioxide (TiO2) nanoparticles have emerged as a promising agent for photocatalytic cancer therapy due to their ability to generate reactive oxygen species (ROS) under ultraviolet (UV) light irradiation. However, the wide bandgap of TiO2 (approximately 3.2 eV for anatase) limits its activation to UV light, which constitutes only a small fraction of solar radiation and has poor tissue penetration. To overcome this limitation, doping strategies and surface modifications have been developed to extend the photocatalytic activity of TiO2 into the visible spectrum while improving tumor selectivity and therapeutic efficacy.

**Doping Strategies for Enhanced Visible Light Absorption**
Nitrogen (N) and carbon (C) doping are among the most effective approaches to reduce the bandgap of TiO2, enabling visible light activation. Nitrogen doping introduces mid-gap states above the valence band, narrowing the bandgap and allowing electron excitation by lower-energy photons. Studies have shown that N-doped TiO2 nanoparticles exhibit absorption edges shifted to around 500 nm, significantly enhancing their photocatalytic activity under visible light. Carbon doping, either substitutional or interstitial, further modifies the electronic structure, often resulting in even broader visible light absorption. The incorporation of carbon can also create oxygen vacancies, which serve as trapping sites for charge carriers, reducing electron-hole recombination and improving ROS generation efficiency.

**Mechanisms of ROS Generation**
Upon photoexcitation, TiO2 nanoparticles generate electron-hole pairs that react with surrounding water and oxygen molecules to produce ROS, including hydroxyl radicals (•OH), superoxide anions (O2•−), and singlet oxygen (1O2). These highly reactive species induce oxidative stress in cancer cells, leading to lipid peroxidation, protein denaturation, and DNA damage, ultimately triggering apoptosis or necrosis. The efficiency of ROS generation depends on the crystallinity, surface area, and defect chemistry of the nanoparticles. Doped TiO2 nanoparticles exhibit prolonged charge carrier lifetimes due to reduced recombination rates, enhancing their photocatalytic performance under visible light.

**Surface Modifications for Tumor Selectivity**
To improve tumor targeting and minimize off-target effects, TiO2 nanoparticles are often functionalized with tumor-specific ligands or coatings. Common strategies include conjugation with folate, peptides, or antibodies that recognize overexpressed receptors on cancer cells. For example, folate-modified TiO2 nanoparticles selectively bind to folate receptor-positive cancer cells, increasing intracellular accumulation and ROS-mediated cytotoxicity. Additionally, surface coatings with polyethylene glycol (PEG) improve biocompatibility and prolong circulation time, facilitating passive tumor targeting via the enhanced permeability and retention (EPR) effect.

**Challenges in Light Penetration Depth**
A major limitation of photocatalytic cancer therapy is the shallow penetration depth of UV and visible light in biological tissues. While visible light penetrates deeper than UV, its effectiveness diminishes beyond a few millimeters, restricting the treatment to superficial or endoscopically accessible tumors. To address this challenge, fiber-optic delivery systems have been developed to guide light directly to deeper-seated tumors. These systems employ diffusing fibers or microlens arrays to distribute light evenly across the tumor site, ensuring sufficient activation of TiO2 nanoparticles. Alternatively, upconversion nanoparticles coupled with TiO2 can convert near-infrared (NIR) light, which penetrates deeper into tissues, into visible or UV light to trigger ROS generation remotely.

**Current Limitations and Future Directions**
Despite promising results, several challenges remain in the clinical translation of TiO2-based photocatalytic therapy. The long-term stability and potential toxicity of doped nanoparticles require thorough investigation. Additionally, optimizing light dosimetry and nanoparticle distribution within tumors is critical to ensure uniform ROS generation and avoid incomplete tumor eradication. Future research may explore combinatorial approaches, such as integrating TiO2 nanoparticles with chemotherapy or immunotherapy, to enhance therapeutic outcomes. Advances in material design, such as dual-doped TiO2 or hybrid nanostructures, could further improve visible light absorption and ROS yields.

In summary, UV/visible-light-activated TiO2 nanoparticles represent a versatile platform for photocatalytic cancer therapy. Through strategic doping, surface modifications, and innovative light delivery systems, these nanoparticles can achieve selective and efficient tumor destruction while overcoming the limitations of conventional photodynamic therapy. Continued refinement of material properties and treatment protocols will be essential to realize their full potential in clinical oncology.