Membrane Fusion Liposome-Mediated Ferroptosis Explosion for Enhanced Cancer Therapy

Ferroptosis, a programmed cell death driven by abundant accumulation of lipid peroxides (LPO), has emerged to be an Achilles' heel for therapy-resistant tumors. However, the curative effect is severely suppressed by insufficient LPO content and defense of intracellular antioxidant systems. Herein, we construct a drug-loaded membrane fusion liposome that can preferentially transfer fatty acid hydroperoxide to cancer cells while simultaneously blocking their agonistic antioxidant systems, thereby promptly inducing excessive LPO accumulation to trigger a "ferroptosis explosion". Sulfasalazine (SSZ), an inhibitor of the cystine/glutamate antiporter (system xc–), dominating intracellular glutathione (GSH) synthesis, is loaded in membrane fusion liposomes that are embellished with linoleic acid hydroperoxide (LAOOH) and cRGD tumor-binding peptide. The enhanced permeability and retention (EPR) effect combined with cRGD binding facilitates oxidative liposomes to selectively accumulate at the tumor upon administration, followed by abundant LAOOH and SSZ delivery to the tumor cells via the membrane fusion mechanism. The resultant instantaneous and overwhelming LPO accumulation not only induces rapid tumor cell ferroptosis but also mediates a "bystander effect" to sensitize adjacent tumor cells to subsequent therapy, bringing about superior tumor inhibition both in vitro and in vivo. Overall, our two-pronged strategy employing an oxidative liposome to rapidly stimulate excessive LPO generation and suppress oxidation defense system represents a promising approach to significantly amplify ferroptosis for treatment of drug-resistant cancer.