Carrier-free doxorubicin nanomedicine integrates chemotherapy and chemodynamic therapy to achieve anti-tumor efficacy.

Nanomedicines have been constructed to enhance the efficacy and safety of traditional anti-cancer drugs. However, the clinical translation of these nanomedicines was hindered by the complexity of carrier materials and functional integration. In this study, a carrier-free nanomedicine composed of doxorubicin (DOX), Cu2+ and siRNA of GPX4 was constructed for combination therapy of tumors. DOX, Cu2+ and siRNA were assembled through multiple forces and decorated with hyaluronic acid (HA) to prepare tumor targeted carrier-free nanomedicines (HDCS). The HA coating on the surface of HDCS ensured specific tumor targeting, and the released drugs triggered by acidity could eliminate tumor cells. The nanomedicine showed significant anti-cancer efficiency and quite reduced side effects in the breast cancer model when compared with DOX solution. HDCS treatment led to significant accelerated production of ROS, reduced GPX4 expression, and sustained decrease in GSH at tumor sites, ultimately forming a powerful chemodynamic effect enhancing circuit. The HDCS provides an effective strategy for tumor combination therapy with good clinical translation and application potential.