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.