Harnessing ROS Amplification and GSH Depletion Using a Carrier‐Free Nanodrug to Enhance Ferroptosis‐Based Cancer Therapy

Abstract Ferroptosis, a non‐apoptotic form of cell death characterized by the production of reactive oxygen species (ROS) and massive accumulation of lipid peroxidation (LPO), shows significant promise in cancer therapy. However, the overexpression of glutathione (GSH) at the tumor site and insufficient ROS often result in unsatisfactory therapeutic efficacy. A multistage, GSH‐consuming, and ROS‐providing carrier‐free nanodrug capable of efficiently loading copper ions (Cu 2+ ), sorafenib (SRF), and chlorogenic acid (CGA) (Cu 2+ ‐CGA‐SRF, CCS‐NDs) is developed to mediate enhanced ferroptosis therapy. Through a reductive intracellular environment, Cu 2+ in the CCS‐NDs reacted with intracellular GSH, alleviating the antioxidant capacity of tumor tissues and triggering the release of drugs. Meanwhile, the released SRF inhibited system xc − , thereby blocking cystine uptake and reducing GSH synthesis in tumor cells. By depleting stored GSH and inhibiting its synthesis, CCS‐NDs achieved efficient GSH depletion and increased accumulation of toxic LPO. More importantly, the high concentration of CGA in the CCS‐NDs induced ROS generation, further promoting ferroptosis. Both in vitro and in vivo results demonstrated that CCS‐NDs effectively triggered ferroptosis in tumor cells by inactivating glutathione peroxidase 4 and inducing LPO. Overall, the carrier‐free nanodrug CCS‐NDs offer a promising strategy for regulating GSH and LPO levels in ferroptosis‐based cancer therapy.