Photothermal-Enhanced Inactivation of Glutathione Peroxidase for Ferroptosis Sensitized by Autophagy Promotor

Up to now, ferroptotic therapeutic strategies remain simplex, though ferroptosis has aroused extensive interest owing to its escape from the biocarriers of conventional therapeutic modalities. Herein, we construct a photothermal (PT)- and autophagy-enhanced ferroptotic therapeutic modality based on MnO2@HMCu2-xS nanocomposites (HMCM) for efficient tumor ablation. The HMCM possess PT-enhanced glutathione (GSH) depletion capability, thereby inducing PT-enhanced ferroptosis via the reinforced inactivation of glutathione peroxidase 4 (GPX4). Thereafter, the GSH-responsed Mn2+ release could generate reactive oxygen species (ROS) by Fenton-like reaction to reinforce the intracellular oxidative stress for the lipid hydroperoxides (LPO) accumulation in ferroptosis. Additionally, an autophagy promotor rapamycin (Rapa) was loaded into HMCM for sensitizing cells to ferroptosis, due to the indispensable role of autophagy in the ferroptosis process. The in vitro and in vivo data demonstrated the HMCM exhibited superio...