Narrow Bandgap Schottky Heterojunction Sonosensitizer with High Electron–Hole Separation Boosted Sonodynamic Therapy in Bladder Cancer

Abstract Sonodynamic therapy (SDT) is applied to bladder cancer (BC) given its advantages of high depth of tissue penetration and nontoxicity due to the unique anatomical location of the bladder near the abdominal surface. However, low electron–hole separation efficiency and wide bandgap of sonosensitizers limit the effectiveness of SDT. This study aims to develop a TiO 2 ‐Ru‐PEG Schottky heterojunction sonosensitizer with high electron–hole separation and narrow bandgap for SDT in BC. Density functional theory (DFT) calculations and experiments collectively demonstrate that the bandgap of TiO 2 ‐Ru‐PEG is reduced due to the Schottky heterojunction with the characteristic of crystalline‐amorphous interface formed by the deposition of ruthenium (Ru) within the shell layer of TiO 2 . Thanks to the enhancement of oxygen adsorption and the efficient separation of electron–hole pairs, TiO 2 ‐Ru‐PEG promotes the generation of reactive oxygen species (ROS) under ultrasound (US) irradiation, resulting in cell cycle arrest and apoptosis of bladder tumor cells. The in vivo results prove that TiO 2 ‐Ru‐PEG boosted the subcutaneous and orthotopic bladder tumor models while exhibiting good safety. This study adopts the ruthenium complex for optimizing sonosensitizers, contributing to the progress of SDT improvement strategies and presenting a paradigm for BC therapy.