Abstract A core‐shell‐structured Cu2O@Mn3Cu3O8 (CMCO) nanozyme is constructed to serve as a tumor microenvironment (TME)‐activated copper ionophore to achieve safe and efficient cuproptosis. The Mn3Cu3O8 shell not only prevents exposure of normal tissues to the Cu2O core to reduce systemic toxicity but also exhibits enhanced enzyme‐mimicking activity owing to the better band continuity near the Fermi surface. The glutathione oxidase (GSHOx)‐like activity of CMCO depletes glutathione (GSH), which diminishes the ability to chelate Cu ions, thereby exerting Cu toxicity and inducing cuproptosis in cancer cells. The catalase (CAT)‐like activity catalyzes the overexpressed H2O2 in the TME, thereby generating O2 in the tricarboxylic acid (TCA) cycle to enhance cuproptosis. More importantly, the Fenton‐like reaction based on the release of Mn ions and the inactivation of glutathione peroxidase 4 induced by the elimination of GSH results in ferroptosis, accompanied by the accumulation of lipid peroxidation and reactive oxygen species that can cleave stress‐induced heat shock proteins to compromise their protective capacity of cancer cells and further sensitize cuproptosis. CMCO nanozymes are partially sulfurized by hydrogen sulfide in the colorectal TME, exhibiting excellent photothermal properties and enzyme‐mimicking activity. The mild photothermal effect enhances the enzyme‐mimicking activity of the CMCO nanozymes, thus inducing high‐efficiency ferroptosis‐boosted‐cuproptosis.
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