Cu-Doped MnO₂ Nanoparticles Loaded with Docetaxel Synergistically Enhance Chemodynamic Therapy through Ferroptosis and Cuproptosis

We have developed an innovative Cu-doped and DTX-loaded Cu-MnO 2 @DTX@FA (MCDF) nanodrug designed to strategically alter tumor microenvironment (TME) by harnessing the synergistic effects of chemodynamic therapy (CDT), chemotherapeutic agents, and the induction of ferroptosis and cuproptosis. The MCDF nanodrug efficiently degrades, releasing abundant Mn 4+, Cu 2+, and DTX. The conversion of Cu 2+ to Cu + facilitated by FDX1 initiates cuproptosis, while, similar to Mn 2+, Cu + reacts with hydrogen peroxide (H 2 O 2 ) to generate hydroxyl radicals (·OH). Cu 2+ and Mn 4+ oxidize glutathione (GSH), significantly depleting GSH levels in tumor cells and inactivating GPX4, which further promotes ferroptosis. The release of Cu 2+ and Mn 4+ intensifies the cuproptosis. DTX effectively disrupts the cell division cycle, thereby inhibiting the proliferation and spread of tumor cells. The FA-modified MCDF is designed to evade immune detection while selectively targeting tumor tissues, ensuring precision in treatment delivery. This cutting-edge material not only provides a multifunctional therapeutic strategy but also sets the stage for the next generation of tumor-targeting nanomedicines.