Mild NIR-II Hyperthermia and Heterojunction Construction Co-Augmented Sonocatalytic Immunotherapy

Reactive oxygen species (ROS)-based treatment strategy, such as sonodynamic and chemodynamic therapy (SDT/CDT), are frequently constrained by the immunosuppressive tumor microenvironment (TME), characterized by hypoxia and high intracellular reductants. Herein, we report the utilization of mild NIR-II photothermal effect as a central coordinator to couple multiple therapeutic modalities and overcome these barriers. To demonstrate this concept, we construct a multifunctional nanoplatform (C-D-CHPB) by anchoring NIR-II-responsive carbon dots (CDs) onto Cu-doped hollow Prussian blue nanocubes (CHPB) and loading DOX into the cavity of CHPB. Rather than relying on direct high-temperature ablation, mild NIR-II photothermal effect (∼43°C) acts as a master coordinator to (i) accelerate nanozyme redox catalysis, amplifying CDT-mediated ROS production while enhancing GSH-ox-like and CAT-like activities to reprogram the TME; (ii) alleviate tumor hypoxia, thereby boosting SDT-mediated ROS generation; and (iii) promote tumor-specific degradation of C-D-CHPB, enabling tumor-specific DOX release and deeper intratumoral penetration. Heterojunction formation between CDs and CHPB further strengthens photothermal conversion, sonodynamic, and multi-enzyme activities through improved electron/energy transfer process, yielding the cascade amplification of ROS production, initiation of ICD, promotion of DC maturation, and activation of T cells. Finally, C-D-CHPB-mediated mild hyperthermia and heterojunction construction co-amplified sono-immunotherapy achieves eradication of primary tumors and inhibition of distant tumors. Overall, this work establishes a mild NIR-II-programmed, heterojunction-augmented synergistic strategy that integrates photothermal, sonodynamic, nanocatalytic, and chemotherapeutic to overcome TME barriers and elicit robust antitumor immune response.