Carbon dot phosphorescent sonosensitizer sensitized copper-based phenolic nanosheets for cuproptosis/sonodynamic/chemodynamic synergistic tumor therapy co-amplified immunotherapy

Controllable degradation behaviors of Cu-based sonosensitizers/nanozymes/cuproptosis-inducers are important for the tumor-specific cuproptosis and accurate sonodynamic therapy (SDT). The fast degradation rate may cause the sonosensitizer to completely degrade before reaching the tumor tissue and conducing SDT, while non-tumor-specific degradation may trigger highly cytotoxic cuproptosis in normal cells. To address these issues, herein, we design the self-assembled Cu-tannic acid (CuTA) as TME-responsive cuproptosis inducers, sonosensitizers, and nanozymes for tumor-specific cuproptosis-enhanced SDT and chemodynamic therapy (CDT). To address the challenge of rapid degradation of CuTA in TME, we further utilize NIR phosphorescent carbon dots (CDs) as the sonosensitizers to amplify the cuproptosis/sonodynamic/chemodynamic properties of CuTA nanosheets. The deposition of CDs not only allows CuTA to complete SDT in tumors before complete degradation but also improves the sonodynamic and multiple enzyme-mimic activity of CuTA nanozymes. In response to acidic TME, CD/CuTA heterojunctions release CDs and Cu ions, leading to the tumor-specific cuproptosis and cascade amplification of ROS generation. Moreover, the significant increase in ROS and cuproptosis effect may reverse immunosuppressive TME, resulting in ICD that could trigger robust systemic immune responses for tumor eradication. This study introduces a novel approach for achieving tumor-specific cuproptosis-augmented sonocatalytic-immunotherapy via controlling the degradation of Cu-based sonosensitizers/nanozymes/cuproptosis-inducers.