Self-enhanced multifunctional nanoplatforms for tumor-specific synergistic therapy via NIR-induced mild photothermal and chemodynamic effects

Multifunctional nanoplatforms that integrate both exogenous stimuli-induced mild photothermal therapy (mPTT) and endogenous stimuli-responsive chemodynamic therapy (CDT) have shown great potential for precise and safe cancer treatment. However, the effective interplay among nanoplatform components to enhance the synergistic effects of mPTT and CDT still suffers from distinct limitations during implementation. Here, we present a novel multifunctional nanoplatform, HCuS-DOX@ZIF-8-GOX (HDZG), rationally engineered to achieve self-augmented mPTT/CDT through cascade regulation under near-infrared (NIR) irradiation, effectively addressing these limitations. Upon accumulation at the tumor site, the synergistic effects of GOX-catalyzed glucose consumption by inhibiting the glycolytic pathway and Zn²⁺-induced mitochondrial dysfunction accelerated adenosine triphosphate (ATP) depletion, thereby suppressing heat shock protein (HSP) expression and amplifying the efficacy of NIR-triggered mPTT. Simultaneously, reactive oxygen species (ROS) production was markedly amplified via an accelerated Fenton-like reaction, driven by elevated intracellular H₂O₂ levels produced from GOX-catalyzed glucose oxidation and the photothermal effect of hollow copper sulfide (HCuS). Moreover, glutathione (GSH) depletion was intensified by DOX-induced ROS production and the Cu⁺/Cu²⁺ cycling reaction, collectively contributing to a markedly improved CDT effect. Consequently, HDZG NPs demonstrated self-enhanced antitumor effects through NIR-induced mild photothermal/chemodynamic synergistic therapy, offering a promising strategy to improve the efficacy of multimodal cancer treatments.