Self‐Accelerating Bimetallic Peroxide Nanozymes for Cascade‐Amplified Pyroptosis‐Immunotherapy

ABSTRACT Despite the promise of hydrogen peroxide (H 2 O 2 )‐mediated cancer therapy, its efficacy is often constrained by the insufficient endogenous H 2 O 2 levels and immunosuppressive tumor microenvironment (TME). To address this, we designed a bimetallic peroxide nanosystem (CuZnONPs) that executes a triple‐combination therapeutic strategy. In the weakly acidic TME, CuZnONPs self‐supply H 2 O 2 , exert enzyme‐mimetic activities to catalyze H 2 O 2 into toxic reactive oxygen species (·OH and ·O 2 − ) and O 2 , and release Zn 2+ to activate pyroptosis. Density functional theory calculations reveal that the single Cu atoms in CuZnONPs play a critical role by not only conferring peroxidase‐like activity for ·OH generation but also modulating the electronic structure of adjacent Zn sites to drive cascade catalase‐ and oxidase‐like activities for ·O 2 − production. The resulting reactive oxygen species burst downregulates the GSH/GPX4 axis, disrupts redox homeostasis, and inflicts extensive damage to lipids, mitochondria, and DNA. Furthermore, Zn 2+ ‐activated pyroptosis elicits damage‐associated molecular pattern release to promote dendritic cells maturation and remodel the inflammatory tumor microenvironment, ultimately converting cold tumors into hot tumors. This work establishes a TME‐responsive nanoplatform that synergistically integrates catalytic therapy with pyroptosis‐enhanced immunotherapy, offering new insights into the design of nanomedicines for cancer therapy.