Cu-doped cerium oxide-based nanomedicine for tumor microenvironment-stimulative chemo-chemodynamic therapy with minimal side effects

CeO₂ nanoenzyme possesses multiple enzyme-mimicking activities and excellent biocompatibility. However, its weak peroxidase (POD)-mimicking property in the tumor microenvironment (TME) hinders its further tumor therapy application. To enhance CeO₂ nanoenzyme's POD activity and overcome limitations of single therapeutic modality, a novel antitumor controlled drug release system (CCCs NPs) was designed using Cu doped cerium oxide nanoparticles (Cu-CeO₂ NPs) loaded with clinical anti-cancer drug doxorubicin (DOX) as the core and the breast cancer cell membrane as the outer shell. Cu doping endowed CeO₂ NPs’ with significantly enhanced POD-mimicking activity in the TME due to a remarkably higher Ce³⁺/Ce⁴⁺ ratio. The cancer cell membrane coating enabled our nanomedicine with homotypic targeting property. Combined with chemotherapeutic drug DOX, a selective and nearly complete tumor suppression was demonstrated in vitro and in vivo. Remarkably, under physiological condition, CCCs NPs worked as a radical scavenger to protect normal cells from oxidative stress caused by anti-cancer drug DOX and ^[rad]OH generated via Fenton-like reaction. Collectively, our CCCs NPs offered a therapeutic potential for effective breast cancer therapy while being free of side effects.