Synergistic Amplification of Ferroptosis with Liposomal Oxidation Catalyst and Gpx4 Inhibitor for Enhanced Cancer Therapy

Abstract As a distinctly different way from apoptosis, ferroptosis can cause cell death through excessive accumulation of lipid peroxide (LPO) and show great potential for cancer therapy. However, efficient strategies for ferroptosis therapy are still facing great challenges, mainly due to insufficient endogenous H 2 O 2 or relatively high pH value for Fenton reaction‐dependent ferroptosis, and the high redox level of tumor cells attenuates the oxidation therapy. Herein, an efficient lipid‐based delivery system to load oxidation catalyst and glutathione peroxidase 4 (Gpx4) inhibitor is orchestrated, intending to amplify Fenton reaction‐independent ferroptosis by bidirectional regulation of LPO accumulation. Ferric ammonium citrate (FAC), Gpx4 inhibitor sorafenib (SF), and unsaturated lipids are constructed into mPEG 2K ‐DSPE‐modified liposomes (Lip@SF&FAC). Influenced by the high level of intratumoral glutathione, FAC can be converted into Fe 2+ , and subsequently the formed iron redox pair (Fe 2+ /Fe 3+ ) catalyzes unsaturated phospholipids of liposomes into LPO via a Fenton reaction‐independent manner. Meanwhile, SF can downregulate LPO reduction by inhibiting Gpx4 activation. In vitro and in vivo antitumor experiments show that Lip@SF&FAC induces massive LPO accumulation in tumor cells and ultimately exhibits strong tumor‐killing ability with negligible side effect. Consequently, this two‐pronged approach provides a new ferroptosis strategy for predominant LPO accumulation and enhanced cancer therapy.