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

AbstractThe introduction of glucose oxidase, exhibiting characteristics of glucose consumption and H2O2 production, represents an emerging antineoplastic therapeutic approach that disrupts nutrient supply and promotes the 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, we present two‐dimensional 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. In addition to mimicking the activities of glutathione peroxidase, catalase, oxidase, and peroxidase, the engineered CMO NSs also 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.This article is protected by copyright. All rights reserved