Interfacial strong interaction-enabling cascade nanozymes for apoptosis-ferroptosis synergistic therapy

Noble metal nanozymes are promising therapeutic agents due to their good ability of reactive oxygen species generation in response to the tumor microenvironment (TME). Achieving optimal performance of noble metal nanozymes at a minimum dosage is crucial due to potential systemic biotoxicity. In this study, we report the successful anchoring of Ir nanoclusters on Co(OH)2 nanosheets with an Ir content of 6.2 wt% (denoted as Ir6.2-Co(OH)2), which exhibits remarkable peroxidase (POD)- and catalase (CAT)-like activities. The strong electronic interaction at the Ir-O-Co interface endows glutathione peroxidase (GSH-Px)-like activity to the composite, ensuring efficient generation of reactive oxygen species (ROS) and deactivation of glutathione peroxidase 4 (GPX4) by supplementing hydrogen peroxide (H2O2) and depleting glutathione (GSH). Both in vitro and in vivo evaluations demonstrate that Ir6.2-Co(OH)2 nanozymes significantly enhance antitumor efficacy through apoptosis-ferroptosis synergistic therapy. This study highlights the tremendous potential of leveraging strong electronic interactions between noble metals and oxides for modulating enzyme-like activities towards high-efficiency synergistic therapies.