H2O2-replenishable and GSH-depletive ROS ‘bomb’ for self-enhanced chemodynamic therapy

Abstract

Chemodynamic therapy (CDT) is an emerging strategy of tumor therapy that utilizes the Fenton reagent to kill tumor cells by disproportionation of H₂O₂ into hydroxyl radical (˙OH). However, insufficient endogenous H₂O₂ confines the antitumor efficacy of CDT. Additionally, the overexpressed glutathione (GSH) exhibits a potent scavenging effect on cytotoxic ˙OH, which further diminishes the efficacy of CDT. Though tremendous efforts have been done, engineering CDT agents with efficient and specific H₂O₂ self-supplying and GSH-depletion is promising but remains a great challenge. Herein, Fe³⁺–chelated CaO₂ nanoparticles (CaO₂–Fe NPs) are constructed as ROS ‘bomb’. In the tumor microenvironment, CaO₂–Fe NPs can release Fe²⁺ by the reduction of GSH, and the remaining CaO₂ reacts with H⁺ to selectively generate H₂O₂. The generated H₂O₂ can produce ˙OH under the catalysis of Fe²⁺ through the Fenton reaction, and re-oxidation from Fe²⁺ to Fe³⁺ endowing a long-lasting GSH-depletion, resulting in an improved CDT. These CaO₂–Fe NPs supply H₂O₂ and exhaust GSH simultaneously to achieve a self-enhanced CDT, and paves an emerging strategy to enhance the therapeutic efficacy of CDT by combining H₂O₂-replenishable and GSH-depletive together and realizing a self-enhanced Fenton reaction cycle.