Self‐Accelerating Bimetallic Peroxide Nanozymes for Cascade‐Amplified Pyroptosis‐Immunotherapy
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
ABSTRACT Despite the promise of hydrogen peroxide (HO)‐mediated cancer therapy, its efficacy is often constrained by the insufficient endogenous HOlevels 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 HO, exert enzyme‐mimetic activities to catalyze HOinto toxic reactive oxygen species (·OH and ·O) and O, and release Znto 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 ·Oproduction. 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‐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. Acidic tumor microenvironment‐responsive CuZnON
Abstract
ABSTRACT Despite the promise of hydrogen peroxide (HO)‐mediated cancer therapy, its efficacy is often constrained by the insufficient endogenous HOlevels 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 HO, exert enzyme‐mimetic activities to catalyze HOinto toxic reactive oxygen species (·OH and ·O) and O, and release Znto 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 ·Oproduction. 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‐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. Acidic tumor microenvironment‐responsive CuZnONPs enable triple‐combination therapy via self‐supplying HO, cascade nanozyme activities for ROS burst, and Zn‐activated pyroptosis, synergizing catalytic therapy with immunotherapy to convert cold tumors into hot ones. advs75441-abs-0001 graphical