2D Catalytic Nanozyme Enables Cascade Enzyodynamic Effect‐Boosted and Ca²⁺ Overload‐Induced Synergistic Ferroptosis/Apoptosis in Tumor

Abstract The introduction of glucose oxidase, exhibiting characteristics of glucose consumption and H₂O₂ production, represents an emerging antineoplastic therapeutic approach that disrupts nutrient supply and promotes efficient generation of reactive oxygen species (ROS). However, the instability of natural enzymes and their low therapeutic efficacy significantly impede their broader application. In this context, 2D Ca₂Mn₈O₁₆ nanosheets (CMO NSs) designed and engineered to serve as a high‐performance nanozyme, enhancing the enzyodynamic effect for a ferroptosis–apoptosis synergistic tumor therapy, are presented. In addition to mimicking activities of glutathione peroxidase, catalase, oxidase, and peroxidase, the engineered CMO NSs exhibit glucose oxidase‐mimicking activities. This feature contributes to their antitumor performance through cascade catalytic reactions, involving the disruption of glucose supply, self‐supply of H₂O₂, and subsequent efficient ROS generation. The exogenous Ca²⁺ released from CMO NSs, along with the endogenous Ca²⁺ enrichment induced by ROS from the peroxidase‐ and oxidase‐mimicking activities of CMO NSs, collectively mediate Ca²⁺ overload, leading to apoptosis. Importantly, the ferroptosis process is triggered synchronously through ROS output and glutathione consumption. The application of exogenous ultrasound stimulation further enhances the efficiency of ferroptosis–apoptosis synergistic tumor treatment. This work underscores the crucial role of enzyodynamic performance in ferroptosis–apoptosis synergistic therapy against tumors.