Dual Vacancies‐Engineered Two‐Dimensional Sonocatalysts for Ultrasound‐Augmented and PANoptosis‐Driven Catalytic Tumor Nanotherapy

ABSTRACT Regulated cell death (RCD) is considered a vital process in cancer therapy, determining treatment outcomes and facilitating the eradication of cancer cells. As an emerging type of RCD, PANoptosis features excellent antineoplastic effects due to its combination of death modes, including pyroptosis, apoptosis, and necroptosis. In this work, anion‐cation vacancies (oxygen/titanium‐vacancy‐rich) ultrathin HTiO nanosheets with outstanding sonocatalytic performance and peroxidase‐mimicking activity are rationally engineered for the disruption of mitochondrial function in tumor cells and the destabilization of redox homeostasis, ultimately inducing tumor PANoptosis. The utilization of external ultrasound energy amplifies the production of toxic reactive oxygen species (ROS). Density functional theory calculations indicate that the oxygen and titanium vacancies generated in HTiO nanosheets enhance the ROS generation efficiency by promoting carrier separation and increasing the adsorption capacity of H 2 O 2 . The advantages of triggering PANoptosis are substantially evidenced by exceptional antineoplastic efficacy both at the cellular level and on two in vivo separate tumor xenografts (4T1 and MDA‐MB‐231 breast tumors). This work highlights a distinct type of titanium‐based nanostructure with a multimodal synergistic integration of sonocatalytic and enzymatic therapies, offering an alternative but highly efficient strategy for fabricating vacancy‐engineered sonocatalytic biomaterials with optimized therapeutic performance in tumor treatment.