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.
Lu et al. (Thu,) studied this question.