Engineering Dual-Responsive Nanoplatform Achieves Copper Metabolism Disruption and Glutathione Consumption to Provoke Cuproptosis/Ferroptosis/Apoptosis for Cancer Therapy

Cuproptosis is a new copper-dependent form of regulated cell death and shows enormous promise in cancer therapy. However, its therapeutic performance is compromised by the strictly regulated copper metabolism and highly expressed intracellular glutathione (GSH). Herein, an intelligent nanoplatform (NSeMON-P@CuT/LipD) is rationally developed as a copper metabolic disrupter, GSH consumer, and Fenton-like reaction trigger for cancer cuproptosis/ferroptosis/apoptosis therapy. NSeMON-P@CuT/LipD is constructed from the preparation of diselenide-bridged mesoporous organosilica nanoparticles, and then pemetrexed (Pem) is loaded followed by surface deposition with a Cu²⁺-3,3'-dithiobis(propionohydrazide) (TPH) coordinated network and coating with a diclofenac (DC)-encapsulated liposome. In response to the specific tumor microenvironment, the obtained NSeMON-P@CuT/LipD can release DC, Cu²⁺, and Pem and simultaneously amplify cellular oxidative stress by consuming GSH and catalyzing endogenous H₂O₂ into hydroxyl radicals (•OH). Both liberated DC and augmented oxidative stress can inhibit glycolysis, reduce ATP level, and then block copper transporter ATP7B, resulting in metabolic disorders and the high retention of copper in cells for •OH generation. Moreover, the overloaded copper can promote dihydrolipoamide <i>S</i>-acetyltransferase oligomerization and Fe-S cluster protein loss, thus evoking cuproptosis. Collectively, the augmented oxidative stress activates prominent ferroptosis, which cooperates with cuproptosis and Pem-mediated apoptosis to significantly inhibit the tumor growth of 4T1 tumor-bearing mice. This study demonstrates feasible strategies to enhance tumor cuproptosis using a single nanoplatform and may also inspire the design of advanced cuproptosis-related therapies.