A self-supplying H(2)O(2) "nano-reaction engine" with photothermal boosting for cascade chemodynamic-immunotherapy.

Chemodynamic therapy (CDT) involves conversion of endogenous hydrogen peroxide (H(2)O(2)) into highly toxic hydroxyl radicals (•OH) for effective tumor ablation. However, the therapeutic efficacy of CDT is severely limited by the insufficient H(2)O(2) levels and excessive glutathione (GSH) within the tumor microenvironment, which collectively establish a redox-protective state that resists oxidative stress. To overcome these intrinsic barriers, we developed a self-supplying H(2)O(2) nanoplatform (CZPI) that enables synergistically enhanced tumor immunotherapy. The CZPI platform features a Cu-ZnO(2) core nanostructure as a "reaction engine", and utilizes sequential surface modification by oxidative self-polymerization of polydopamine (PDA) and π-π stacking of indocyanine green (ICG) to introduce a high-efficiency photothermal "booster." In the weakly acidic TME, ZnO(2) undergoes acid-triggered decomposition to release H(2)O(2) and Cu(2+) ions. The latter react with intracellular GSH to generate Cu (+) ions, which catalyze the Fenton-like decomposition of H(2)O(2) to continuously produce •OH while regenerating Cu(2+) for redox cycling. Furthermore, the synergistic photothermal effect of PDA and ICG increases local temperature in response to near-infrared (NIR) irradiation, thereby accelerating reaction kinetics and amplifying the cascade reaction. This photothermal-chemodynamic action of CZPI induces multiple forms of programmed cell death - including apoptosis, ferroptosis, and immunogenic cell death (ICD) - which subsequently activate systemic anti-tumor immune responses. Overall, this study presents a novel "reaction engine-booster" paradigm that integrates self-supplying H(2)O(2) generation with photothermal acceleration, offering a powerful platform for multimodal synergistic cancer therapy and durable immune activation.