Self-Boosting Cuproptosis-Based Synergistic Antitumor Therapy by GSH-Enhanced Cocatalysis and Copper Efflux Inhibition

Cuproptosis efficiency is severely limited by insufficient Cu + contents in tumors due to the easy oxidation of Cu + into Cu 2+ and the copper efflux mechanism. Herein, we develop a copper nanocarrier (MoSe 2 /CuO 2 ) that can significantly enhance intracellular Cu + for self-boosting cuproptosis-based synergistic antitumor therapy. Upon endocytosis by cancer cells, the acidic tumor microenvironment (TME) triggers the degradation of MoSe 2 /CuO 2 to release Cu 2+ . MoSe 2 then acts as a cocatalyst that promotes the reduction of released Cu 2+ to Cu +, while oxidizing active Mo 4+ to Mo 6+, thereby triggering cuproptosis. Importantly, the produced Mo 6+ is further returned to Mo 4+ by endogenous glutathione (GSH) depletion, enhancing the cocatalytic effects of MoSe 2 and resulting in a continuous Cu + generation for self-boosting cuproptosis. Meanwhile, GSH-enhanced cocatalysis and MoSe 2 -mediated photothermal effect can significantly promote Cu-Fenton reactions, which not only downregulate Cu-ATPase to reduce Cu + efflux and aggravate cuproptosis with higher efficacy but also activate caspase-3 to promote cell apoptosis. MoSe 2 /CuO 2 exhibits excellent antitumor effects (94.9% tumor growth inhibition) and biosafety effects in vitro and in vivo . This work presents a strategy that enables high levels of Cu + delivery by enhancing generation and reducing efflux for self-boosting cuproptosis–apoptosis synergistic therapy.