Boosting Ferroptosis Therapy with Iridium Single‐Atom Nanocatalyst in Ultralow Metal Content

Abstract Nanocatalysts are promising tumor therapeutics due to their ability to induce reactive oxygen species in the tumor microenvironment. Although increasing metal loading can improve catalytic activity, the quandary of high metal content versus potential systemic biotoxicity remains challenging. Here, a fully exposed active site strategy by site‐specific anchoring of single iridium (Ir) atoms on the outer surface of a nitrogen‐doped carbon composite (Ir single‐atom catalyst (SAC)) is reported to achieve remarkable catalytic performance at ultralow metal content (≈0.11%). The Ir SAC exhibits prominent dual enzymatic activities to mimic peroxidase and glutathione peroxidase, which catalyzes the conversion of endogenous H 2 O 2 into •OH in the acidic TME and depletes glutathione (GSH) simultaneously. With an advanced support of GSH‐trapping platinum(IV) and encapsulation with a red‐blood‐cell membrane, this nanocatalytic agent (Pt@IrSAC/RBC) causes intense lipid peroxidation that boosts tumor cell ferroptosis. The Pt@IrSAC/RBC demonstrates superior therapeutic efficacy in a mouse triple‐negative mammary carcinoma model, resulting in complete tumor ablation in a single treatment session with negligible side effects. These outcomes may provide valuable insights into the design of nanocatalysts with high performance and biosafety for biomedical applications.