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

Despite the promise of hydrogen peroxide (H₂O₂)-mediated cancer therapy, its efficacy is often constrained by the insufficient endogenous H₂O₂ 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 H₂O₂, exert enzyme-mimetic activities to catalyze H₂O₂ into toxic reactive oxygen species (·OH and ·O₂ ^-) and O₂, and release Zn²⁺ 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 ·O₂ ^- 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, Zn²⁺-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.