Dual‐Active Center AgFeCu Nanocatalyst for Tumor Destruction via Self‐Catalytically Enhanced Mild Photothermal Therapy

Abstract Mild photothermal therapy (mPTT) has emerged as a highly promising approach for tumor ablation. However, the heat‐induced overexpression of heat shock proteins (HSPs) limits its efficacy by increasing cellular temperature tolerance. Herein, a self‐catalytically enhanced mild PTT strategy that directly disrupts the structure of HSPs to restore tumor cell sensitivity is proposed. In the proof‐of‐concept study, AgFeCu nanoparticles (AgFeCu NPs) with dual‐active catalytic centers (Fe‐Cu) and near‐infrared photothermal properties are developed. The AgFeCu NPs can efficiently catalyze the conversion of endogenous hydrogen peroxide into hydroxyl radicals in situ, leading to the degradation of HSPs and enhancing the therapeutic effects of mild PTT mediated by their Ag‐based substrates. Furthermore, AgFeCu NPs can also induce oxidative stress by depleting intracellular glutathione and promoting lipid peroxidation, thereby triggering tumor ferroptosis and resulting in significant tumor elimination in a U87MG murine tumor model. This self‐catalytically enhanced strategy maximizes the efficacy of mild PTT while minimizing damage to healthy tissues, which is expected to provide valuable insights for the development of next‐generation photothermal nanoagents for improved tumor therapeutics.