Hybrid TiO₂–Ruthenium Nano-photosensitizer Synergistically Produces Reactive Oxygen Species in both Hypoxic and Normoxic Conditions

Photodynamic therapy (PDT) is widely used to treat diverse diseases, but its dependence on oxygen to produce cytotoxic reactive oxygen species (ROS) diminishes the therapeutic effect in a hypoxic environment, such as solid tumors. Herein, we developed a ROS-producing hybrid nanoparticle-based photosensitizer capable of maintaining high levels of ROS under both normoxic and hypoxic conditions. Conjugation of a ruthenium complex (N3) to a TiO₂ nanoparticle afforded TiO₂-N3. Upon exposure of TiO₂-N3 to light, the N3 injected electrons into TiO₂ to produce three- and four-fold more hydroxyl radicals and hydrogen peroxide, respectively, than TiO₂ at 160 mmHg. TiO₂-N3 maintained three-fold higher hydroxyl radicals than TiO₂ under hypoxic conditions via N3-facilitated electron–hole reduction of adsorbed water molecules. The incorporation of N3 transformed TiO₂ from a dual type I and II PDT agent to a predominantly type I photosensitizer, irrespective of the oxygen content.