Glutathione‐Induced In Situ Oxygen Vacancies in FeOOH Nanospindles for Boosting Sonocatalytic Tumor Therapy

ABSTRACT Defect engineering can enhance carrier separation in sonocatalysts to boost reactive oxygen species (ROS) generation; however, the current methods still rely on in vitro physicochemical defect introduction that lacks tumor specificity and poses a risk of off‐target activation. Herein, we developed FeOOH nanospindles in which glutathione (GSH) within tumor cells triggers the formation of in situ oxygen vacancies (O vac ), promoting ROS generation during sonocatalytic therapy (SCT) to enhance antitumor efficacy while minimizing off‐target toxicity. The introduction of O vac narrows the bandgap, raises the Fermi level, promotes charge separation, and inhibits electron‐hole recombination, thereby significantly enhancing the sonocatalytic production of 1 O 2 . Concurrently, Fe 3+ ions catalyze oxygen evolution to alleviate tumor hypoxia, while Fe 3+ ions are reduced to Fe 2+ ions by GSH, which mediate the Fenton reaction, generating toxic •OH under ultrasound irradiation. This “three‐in‐one” design ingeniously integrates tumor microenvironment (TME) responsiveness, in situ defect engineering, and multiple catalytic mechanisms to disrupt redox homeostasis and trigger apoptosis and ferroptosis synergistically. By enabling in situ activation and site‐specific amplification of therapeutic functions, this work offers a great promise for advancing precision oncology and overcoming the current limitations of ROS‐based tumor therapies.