Boosting Ferroptosis Therapy with Iridium Single Atom Nanocatalyst in Ultra-low Metal Content.

Nanocatalysts pose great promise as tumor therapeutic agents due to their potent capacity to induce reactive oxygen species (ROS) in tumor microenvironment (TME). Although increasing metal loading can improve the catalytic activity, addressing the dilemma between high metal content and potential systemic biotoxicity it poses still remains a great challenge. Here, we report a fully exposed active site strategy by site-specific anchoring single iridium (Ir) atoms on the outer surface of nitrogen-doped carbon composite (Ir SAC) to obtain notable catalytic performance in an ultra-low metal content (∼ 0.11%). Ir SAC exhibited prominent dual enzymatic activities to mimic peroxidase (POD) and glutathione peroxidase (GSHOx), which can catalyze the conversion of endogenous H 2 O 2 into •OH in the acidic TME and deplete glutathione (GSH) simultaneously. With advanced support of a GSH-trapping platinum(IV), this nanocatalytic agent (Pt@IrSAC) caused intense lipid peroxidation that boosted tumor cell ferroptosis. Pt@IrSAC was further encapsulated with the membrane of red blood cells (Pt@IrSAC/RBC) to improve biocompatibility and biodistribution of nanocatalysts in vivo. The Pt@IrSAC/RBC demonstrated superior therapeutic efficacy in a mouse triple-negative mammary carcinoma model, resulting in complete tumor ablation in a single treatment session and negligible side effects. To our best knowledge, this is the first report on an ultra-low metal content Ir single atom catalyst for tumor ferroptosis therapy, which may provide valuable insights into the design of nanocatalysts with high performance and biosafety for biomedical applications. This article is protected by copyright. All rights reserved.