Ruthenium Single‐Atom Nanozyme Driven Sonosensitizer with Oxygen Vacancies Enhances Electron–Hole Separation Efficacy and Remodels Tumor Microenvironment for Sonodynamic‐Amplified Ferroptosis

Sonodynamic therapy (SDT) has emerged as a promising noninvasive approach for tumor therapy. However, the effectiveness of traditional inorganic semiconductor sonosensitizers is hindered by rapid electron (e^-) and hole (h⁺) recombination under ultrasonic (US) stimulation, as well as the hypoxic and reductive conditions of tumor microenvironment (TME), which limit the generation of reactive oxygen species (ROS). Herein, a ruthenium (Ru) single-atom nanozyme-driven superimposition-enhanced titanium dioxide-based sonosensitizer (Ru/TiO_2-x SAE) is presented that features sufficient oxygen vacancies and high e^-/h⁺ separation efficiency. Through synchrotron radiation-based X-ray absorption spectroscopy and extended X-ray absorption fine structure analysis it is confirmed that oxygen vacancies in TiO_2-x nanoparticles promote the immobilization of single-atomic Ru, forming Ru-O₄ active sites. Density functional theory calculations demonstrate that oxygen vacancies alter the electronic structure of nanosensitizer, enhanced e^-/h⁺ separation, increasing oxygen adsorption, and accelerating reaction kinetics under US stimulation, ultimately improving ROS production. Moreover, Ru/TiO_2-x SAE boosts sonodynamic efficacy by mitigating the hypoxic and reductive TME. This is attributed to its catalase- and glutathione peroxidase 4-like activities, which facilitate the generation of ROS and trigger lipid peroxidation-mediated ferroptosis. These findings highlight the innovative role of single-atom Ru in optimizing sonosensitizers for SDT-induced ferroptosis, demonstrating its potential for advancing cancer therapy.