Single-atom nanozyme-mediated dihydroartemisinin delivery for self-enhanced chemodynamic therapy and ferroptosis

Chemodynamic therapy (CDT), leveraging intracellular iron ions (Fe²⁺) and hydrogen peroxide (H₂O₂), is a highly selective therapeutic strategy with significant potential. However, its clinical application is currently hindered by the limited catalytic activity of transition metal ions and insufficient H₂O₂ supply. In this study, we present a novel and effective CDT approach using an Fe single-atom nanozyme (Fe-SAE) to deliver dihydroartemisinin (DHA), a first-line antimalarial drug. DHA serves dual roles: as a substitute for H₂O₂ and as a recruiter of Fe³⁺, significantly enhancing the reactive oxygen species (ROS) cascade for self-amplified chemodynamic and ferroptosis therapy. Upon internalization by tumor cells, Fe-SAE, with its atomically dispersed active sites, exhibits remarkable peroxidase-like activity, catalyzing the generation of hydroxyl radicals from H₂O₂. Simultaneously, the endoperoxide bridge in released DHA is cleaved by Fe-SAE, further generating ROS and inducing lethal lipid peroxidation. DHA also upregulates the expression of transferrin receptor 1 (TfR1), facilitating Fe³⁺ influx and increasing intracellular Fe³⁺ levels, thereby enhancing chemodynamic efficacy. Additionally, Fe-SAE@D demonstrates glutathione oxidase-like activity, oxidizing reductive GSH to glutathione disulfide and promoting GPX4 inactivation. Both in vitro and in vivo studies confirm that Fe-SAE@D induces CDT and ferroptosis by self-supplying H₂O₂, initiating a ROS storm, and depleting glutathione. These synergistic effects significantly enhance CDT efficacy, presenting a promising strategy to overcome traditional CDT limitations.