Thermally Gated Dual-Cascade Nanozyme for Enhanced Mild-Temperature Photothermal Therapy

Mild-temperature photothermal therapy (mPTT) is attractive for cancer treatment due to its safety and precision but is limited by heat shock protein 70 (HSP70)-mediated thermotolerance, which allows tumor cells to survive sublethal heating. Herein, a thermo-responsive cascade nanozyme system is reported (Ru-GOx-PNN) that enhances mPTT through dual suppression of HSP70. This system integrates a Ru-doped porous carbon framework that serves as both an efficient NIR photothermal transducer and a catalytic nanozyme with intrinsic peroxidase (POD)- and catalase (CAT)-like activities, immobilized glucose oxidase (GOx) to initiate metabolic oxidation and supply H₂O₂, and an outer thermosensitive PNN hydrogel that gates substrate access and exposes active sites specifically within the mPTT window. Upon mild heating, the GOx-POD cascade generates hydroxyl radicals that trigger lipid peroxidation and destabilize HSP70, while the GOx-CAT cascade consumes glucose and reduces adenosine triphosphate synthesis, further suppressing HSP70 expression. The resulting inhibition of HSP70 relieves its restraint on c-Jun N-terminal kinase signaling, thereby amplifying apoptosis. Collectively, this strategy effectively overcomes thermal resistance and enhances the therapeutic efficacy of mPTT. This study highlights the potential of cascade catalytic nanozymes as intelligent platforms for safe, efficient, and precise tumor therapy, particularly in challenging malignancies such as esophageal squamous cell carcinoma (ESCC).