Iron-vacancy-tailored sonosensitive catalysts amplify noninvasive tumor suppression by apoptosis/pyroptosis co-induction.

Sonocatalytic therapy has emerged for efficient malignant tumor treatment due to its non-invasive characteristics, spatiotemporal precision, and deep tissue penetration capabilities. The defect engineering can improve charge carrier separation, and enhance reactive oxygen species (ROS) generation, but the current technological limitations in developing efficient hole trapping sites relative to electron traps still impose significant constraints on overall ROS production efficiency. In this work, the rational design of two-dimensional Fe-vacancy (FeV)-engineered FeOCl nanosheets (FeVOCl NSs) with iron vacancies enables simultaneous electron and hole (e--h+) trapping, which confers not only significantly enhanced sonocatalytic activity but also multienzyme-mimicking properties, including peroxidase-, oxidase-, and catalase-like activities. These capabilities collectively promote ROS generation, relieve tumor hypoxia, and reshape the tumor microenvironment. Density functional theory (DFT) calculations reveal that strategically engineered iron vacancies in FeVOCl NSs significantly improve ROS generation efficiency through facilitating charge carrier separation and increasing H2O2 adsorption capacity. This dual functionality under ultrasound (US) irradiation leads to efficient ROS-mediated activation of both apoptotic and pyroptotic cell death pathways in tumor cells, which achieve significant in vivo sonocatalytic tumor-eliminating capacity and efficacy across multiple cancer models, including hematologic and breast cancer. These findings highlight the essential role of strategic defect engineering coupled with enzyme-mimicking activity in optimizing sonocatalytic therapeutic outcomes for efficient cancer treatment.