Chemodynamic therapy (CDT) is widely explored for tumor-specific therapy by converting endogenous H 2 O 2 to lethal •OH to destroy cancer cells. However, •OH scavenging by glutathione (GSH) and insufficient intratumoral H 2 O 2 levels seriously hinder the application of CDT. Herein, we reported the fabrication of copper ion-doped ZIF-8 loaded with gold nanozymes and doxorubicin hydrochloride (DOX) for the chemotherapy and CDT synergistic treatment of tumors with the assistance of tumor microenvironment (TME)-activated fluorescence imaging. The Cu 2+ -doped ZIF-8 shell was gradually degraded to release DOX and gold nanoclusters responding to the acidic TME. The fluorescence signal of the tumor region was acquired after the quenched fluorescence of the gold nanoclusters by Cu 2+ and DOX by aggregation-induced quenching was turned on because of the interaction of GSH with Cu 2+ and the release of free DOX. The Cu 2+ ions could deplete the GSH via redox reactions and the generated Cu + could convert internal H 2 O 2 to •OH for tumor CDT. The chemotherapeutic effect of DOX was strengthened through drug efflux inhibition and drug sensitivity increase due to the consumption of GSH and •OH burst. Moreover, DOX could raise the level of H 2 O 2 and augment the effect of CDT. In addition, the fluorescent gold nanoclusters not only served as a peroxidase to convert H 2 O 2 to •OH but also employed as an oxidase to consume GSH, resulting in the amplification of chemotherapy and CDT. This work presents an approach to construct tumor microenvironment-activated theranostic probes without external stimuli and to achieve the tumor elimination through cascade reactions and synergistic treatment.

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