Biodegradable Cu-based sonozymes for tumor-specific cuproptosis-enhanced sono-immunotherapy through activating cGAS-STING pathway and sensitizing immune checkpoint blockade.

Promoting the maturation of dendritic cells (DCs) is crucial for effectively activating the adaptive immune response. Nevertheless, DC maturation and subsequent antigen presentation were impeded by the immunosuppressive tumor microenvironments (TME). Herein, a cascade amplification strategy for the activation of antitumor immune response is reported for the first time based on a biodegradable Cu-based sonozyme, which integrates ROS-mediated immunogenic cell death (ICD), immune checkpoint blockade (ICB), cuproptosis, and cGAS-STING activation. An in-situ phosphating strategy was employed to synthesize Cu3P sonozymes from Cu2O nanocubes. Different from the pristine Cu2O, the obtained Cu3P nanocubes possess the TME-responsive degradation features, which can only degrade in tumor cells and cannot degrade in normal cells. By virtue of the TME-responsive degradation behaviors, a bioactive triterpenoid with reported antitumor activity (Cel) is then loaded on the surface of Cu3P nanocubes to achieve the tumor-specific drug release. In addition, Cu3P sonozymes exhibited higher sonodynamic and chemodynamic activities owing to the decreased bandgap and improved electronic structure. Immunosuppressive TME can be reversed by the cascade amplification ROS generation efficiency and tumor-specific cuproptosis. The tumor-specific cuproptosis can not only induce ICD, but also increase the expression of PD-LI in tumor cells and then sensitizes the ICB-mediated tumor therapy. Furthermore, Cu3P-mediated cuproptosis activates the cGAS-STING pathway and realizes the cascade amplification of antitumor immune response. This study introduces a new approach to achieve tumor-specific cuproptosis-enhanced sono-immunotherapy through activating cGAS-STING pathway and sensitizing ICB.