A co-delivery nanoplatform dismantling parallel lipid peroxidation defenses from interface to bilayer for triple-negative breast cancer ferroptosis

Ferroptosis, driven by lethal lipid peroxidation (LPO), represents a promising therapeutic strategy for triple-negative breast cancer (TNBC). However, its efficacy is severely compromised by spatially distinct cellular antioxidant defense systems, particularly the cytosolic glutathione (GSH) and the membrane-bound coenzyme Q (CoQ). To dismantle these parallel LPO defenses from the aqueous interface to the hydrophobic bilayer, we developed a coordinated strategy utilizing an albumin-based nanoplatform (H-FS NPs) for the co-delivery of sorafenib and fluvastatin. Mechanistically, sorafenib suppresses cytoplasm GSH levels by inhibiting the xCT subunit, thereby dismantling the GSH-glutathione peroxidase 4 (GPX4) pathway. Concurrently, fluvastatin inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) activity in the mevalonate pathway, thereby reducing CoQ synthesis and disrupting the intrinsic anti-peroxidation defense within the lipid bilayer. Synchronously dismantling these compartmentalized defense systems ignites a self-amplifying LPO cascade, resulting in potent ferroptosis and profound tumor suppression in TNBC models. This work highlights that dismantling spatially compartmentalized antioxidant barriers is a powerful therapeutic strategy for TNBC treatment.