Peroxidase‐Mimicking Iron‐Based Single‐Atom Upconversion Photocatalyst for Enhancing Chemodynamic Therapy

Abstract Chemodynamic therapy (CDT) has emerged as a novel approach to overcome cancer resistance and enhance anticancer efficacy. Despite the considerable effort devoted to current chemodynamic therapeutic agents, developing efficient delivery systems to induce ferroptosis remains demanding due to their limited efficacy and lack of selectivity. Herein, an iron‐based single‐atom upconversion photocatalyst (UmFe‐OA@hPM) mimicking natural horseradish peroxidases has been developed. This nanoformulation not only targets tumors via the existence of a hybrid platelet membrane (hPM) coating but also generates excessive hydroxyl radicals in response to both tumor microenvironment and external laser irradiation. This nanoenzyme overcomes the low tissue penetration of UV light, which sensitizes the iron‐doped graphitic carbon nitride network, attributed to the unique anti‐Stokes shift from infrared to UV displayed by upconversion nanoparticles. Together with an increase in intracellular polyunsaturated fatty acid accumulation induced by oleanolic acid (OA), lipid peroxidation is significantly elevated, leading to the enhancement of CDT. UmFe‐OA@hPM is demonstrated to induce significant ferroptosis in vitro, superior antitumor efficacy in breast cancer mouse models, and suppression of metastasis status when incorporated with an immune checkpoint blockade. These findings provide a potential strategy for developing a precisely controlled CDT to deal with aggressive cancers, especially in combination with immunotherapy.