Combining H2O2-SupplyingIron Peroxide Nanoclusters with GSH-Depleting Gold Nanoclusters forEnhanced Chemodynamic Therapy via Amplification of Oxidative Stress

Abstract Chemodynamic therapy (CDT), which employs •OH generated by Fenton-type reactions to trigger cancer cell death, has received much attention in recent years. However, CDT efficacy is restricted by insufficient H2O2 levels and reactive oxygen species (ROS) consumption by antioxidants in tumor cells. Amplification of intracellular oxidative stress is an effective strategy for enhancing CDT efficiency. In this study, chitosan (CS)-protected iron peroxide nanoclusters (CS@FeNCs) were prepared via the reaction of Fe2+ and H2O2 in CS medium, and the resulting product can release H2O2 and convert H2O2 to •OH through the Fenton reaction under acidic conditions. To suppress the consumption of ROS by glutathione (GSH), gold nanoclusters templated by histidine (His) (His@AuNCs) were used to scavenge intracellular GSH by forming GSH@AuNCs. Furthermore, a nanocomposite was fabricated by encapsulating CS@FeNCs and His@AuNCs with polyvinylpyrrolidone (PVP), and the resulting PVP@Fe–Au can effectively amplify the level of oxidative stress in tumor cells by providing H2O2 and depleting GSH, which induced cancer cell apoptosis and death. It is hoped that the developed PVP@Fe–Au can provide an efficient strategy for designing high-efficiency CDT agents via boosting ROS generation and suppressing the antioxidation system.