Redox Homeostasis Disruptors Based on Metal‐Phenolic Network Nanoparticles for Chemo/Chemodynamic Synergistic Tumor Therapy through Activating Apoptosis and Cuproptosis

Abstract The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal‐phenolic network nanoparticles (NPs) self‐assembled from copper ions and gallic acid (Cu‐GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu‐GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu + and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton‐like reaction of released Cu + , which disrupts redox homeostasis and achieves apoptosis‐related chemodynamic therapy. Moreover, massive accumulation of Cu + in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S‐acetyltransferase and downregulation of iron‐sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu‐GA NPs. The experiments in vivo further demonstrate that Cu‐GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. These Cu‐based metal‐phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy.