A pH/GSH dual-responsive ZnO2@Cu-PDA nanoplatform for synergistic therapy of breast cancer.

Abstract

ROS-driven catalytic therapy holds great promise for cancer treatment, yet its therapeutic performance is severely hampered by insufficient endogenous H2O2. A core-shell ZnO2@Cu-PDA nanoplatform, composed of an acid-labile zinc peroxide core and a copper-enriched amorphous polydopamine shell, was investigated to enable pH/GSH dual-responsive activity. ZCP maintains favorable stability under physiological conditions and undergoes degradation in acidic tumor milieu, achieving localized on-demand release of H2O2 and catalytically active copper ions. The liberated copper ions initiate Fenton-like reactions to convert H2O2 into cytotoxic hydroxyl radicals, and simultaneously deplete intracellular GSH to further boost oxidative stress. The in vitro experiments reveal that ZCP treatment induces mitochondrial damage and robust apoptosis. In vivo assays confirm that ZCP exerts marked tumor growth inhibition. Mechanistically, it induces cuproptosis and reprograms the immunosuppressive TME. This work establishes a synergistic nanotherapeutic strategy integrating catalytic therapy, cuproptosis and immune activation, providing new insights for developing TME-responsive nanomedicine.

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