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

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Abstract
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 [email protected] 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 superior anticancer effect in human breast cancer models, and the combination therapeutic system afford the next generation of ferroptotic therapy for combatting malignant tumor.
Funding Information
  • National Natural Science Foundation of China (21371031, 21628101)
  • Department of S and T for Social Development (2015DFG42240)
  • Priority Academic Program Development of Jiangsu Higher Education Institutions

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