Defect‐engineered iron single‐site catalysts with tailored atomic coordination for enhanced mild photothermal therapy via triad modulation of apoptosis and ferroptosis

Abstract Mild photothermal therapy (MPTT) has emerged as a promising approach for cancer treatment. However, the rapid overexpression of heat shock proteins (HSPs) in cancer cells reduces its therapeutic efficacy. While strategies to suppress HSP expression or induce alternative cell death mechanisms, such as ferroptosis, show potential, overall outcomes remain suboptimal. In this study, we propose a triad material comprising defect‐engineered single‐site catalysts (DMOF), sodium nitroprusside, and HSP‐targeting siRNA. Upon light exposure, this DMOF‐SNP‐siRNA (DSS) catalyst efficiently generates reactive species, suppresses HSP expression, and depletes intracellular glutathione, thereby inducing strong apoptotic and ferroptotic responses simultaneously. Compared to a defect‐free metal‐organic frameworks catalyst, the DSS single‐site catalyst demonstrates significantly enhanced photothermal and catalytic properties, leading to remarkable tumor‐killing capability while minimizing systemic toxicity. Notably, in a subcutaneously grafted tumor model, 60% of treated mice achieved complete remission after just two treatment sessions. Our findings establish a pioneering approach in the design of high‐performance triad materials for advanced MPTT applications.