A heterojunction-engineering nanodrug with tumor microenvironment responsiveness for tumor-specific cuproptosis and chemotherapy amplified sono-immunotherapy.

Abstract

Cuproptosis has recently identified as a unique copper-dependent cell death mechanism that may provide new opportunities for improving the therapeutic effect of tumor therapy through triggering efficient adaptive immune responses. However, the poor delivery efficiency and non-tumor-specific release of Cu ions would restrict the potential clinical applications of cuproptosis inducers. Herein, we report for the first time the development of hollow Cu_2-xSe nanocubes as the tumor microenvironment (TME)-responsive drug delivery systems and cuproptosis inducers for tumor-specific chemotherapy and cuproptosis. The presence of Cu vacancy endows Cu_2-xSe with excellent sonodynamic and chemodynamic activity. The hollow Cu_2-xSe nanocubes with TME-responsive degradation behaviors are further utilized to load graphene quantum dot (GQD) nanodrugs to form GQD/Cu_2-xSe heterojunctions for achieving tumor-specific chemotherapy. The heterojunction-fabrication GQD/Cu_2-xSe exhibits amplified ROS generation capabilities and improved TME regulation ability owing to the optimized electron-hole separation kinetics. More importantly, the significant increase in ROS levels and efficient cuproptosis could reverse the immunosuppressive TME and induce immunogenic cell death that stimulates strong systemic immune responses to eliminate tumors. Collectively, this work presents an innovative strategy for the utilization of TME-responsive cuproptosis inducers for tumor-specific chemotherapy and cuproptosis augmented sono-immunotherapy.