Membrane Fusion Liposome-Mediated Ferroptosis Explosion for Enhanced Cancer Therapy

Ferroptosis, a programmed cell death driven by abundantaccumulationof lipid peroxides (LPO), has emerged to be an Achilles' heelfor therapy-resistant tumors. However, the curative effect is severelysuppressed by insufficient LPO content and defense of intracellularantioxidant systems. Herein, we construct a drug-loaded membrane fusionliposome that can preferentially transfer fatty acid hydroperoxideto cancer cells while simultaneously blocking their agonistic antioxidantsystems, thereby promptly inducing excessive LPO accumulation to triggera "ferroptosis explosion". Sulfasalazine (SSZ), an inhibitorof the cystine/glutamate antiporter (system xc(-)),dominating intracellular glutathione (GSH) synthesis, is loaded inmembrane fusion liposomes that are embellished with linoleic acidhydroperoxide (LAOOH) and cRGD tumor-binding peptide. The enhancedpermeability and retention (EPR) effect combined with cRGD bindingfacilitates oxidative liposomes to selectively accumulate at the tumorupon administration, followed by abundant LAOOH and SSZ delivery tothe tumor cells via the membrane fusion mechanism.The resultant instantaneous and overwhelming LPO accumulation notonly induces rapid tumor cell ferroptosis but also mediates a "bystandereffect" to sensitize adjacent tumor cells to subsequent therapy,bringing about superior tumor inhibition both in vitro and in vivo. Overall, our two-pronged strategyemploying an oxidative liposome to rapidly stimulate excessive LPOgeneration and suppress oxidation defense system represents a promisingapproach to significantly amplify ferroptosis for treatment of drug-resistantcancer.