Dual-site co-valence cycling nanozyme for boosted cuproptosis and triple-modal photo-catalytic-immunotherapy via redox homeostasis imbalance.

Abstract

Disrupting redox homeostasis is a feasible strategy for reversing immunosuppressive tumor microenvironment. Herein, by coating copper selenide (Cu2-xSe) on the surface of gold/molybdenum (AuMo), a AuMo@Cu2-xSe nanozyme with triple-enzyme activities of glucose oxidase/glutathione peroxidase/peroxidase was reported for inducing immunogenic cell death (ICD) and cuproptosis, thereby enhancing antitumor immunotherapy. Benefiting from the reversible valence transition of Mo6+/Mo4+ and Cu2+/Cu+, and the multi-enzyme activities, the reactive oxygen species (ROS) generation was enhanced, and the near-infrared II photothermal performance further promoted ROS generation, ultimately disrupting redox homeostasis. Moreover, by combining ROS storm and Cu2+ transportion, the mitochondrial dysfunction was triggered, which activated ICD and cuproptosis, releasing damage related molecular patterns and regulating cuproptosis-related proteins. Under a 1064 nm laser irradiation, the AuMo@Cu2-xSe nanozyme facilitated dendritic cells maturation, T cells infiltration, M1 macrophages polarization, and memory and regulatory T cells production. The developed AuMo@Cu2-xSe nanozyme provided a feasible strategy of integrating cuproptosis and photo/catalytic/immunotherapy, significantly suppressing primary and metastatic tumors for breast cancer.