A self-supplying H₂O₂ "nano-reaction engine" with photothermal boosting for cascade chemodynamic-immunotherapy

Chemodynamic therapy (CDT) involves conversion of endogenous hydrogen peroxide (H₂O₂) into highly toxic hydroxyl radicals (•OH) for effective tumor ablation. However, the therapeutic efficacy of CDT is severely limited by the insufficient H₂O₂ 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 H₂O₂ nanoplatform (CZPI) that enables synergistically enhanced tumor immunotherapy. The CZPI platform features a Cu-ZnO₂ 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, ZnO₂ undergoes acid-triggered decomposition to release H₂O₂ and Cu²⁺ ions. The latter react with intracellular GSH to generate Cu ⁺ ions, which catalyze the Fenton-like decomposition of H₂O₂ to continuously produce •OH while regenerating Cu²⁺ 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 H₂O₂ generation with photothermal acceleration, offering a powerful platform for multimodal synergistic cancer therapy and durable immune activation.