Cell Membrane-Cloaked Polymeric Nanosystems Stabilize Vulnerable Plaques by Isolating Pro-Ferroptotic Phospholipids and Rescuing Macrophage viability

Background The progression of atherosclerosis is driven by the continuous accumulation of macrophage foam cells and their subsequent demise via ferroptosis—an iron-dependent, lipid peroxidation-driven form of cell death that expands the necrotic core. However, the clinical translation of anti-ferroptotic agents is severely hindered by poor localization to the vascular intima and rapid systemic clearance. Here, we engineered macrophage-biomimetic nanoparticles loaded with curcumin (Cum@MM-NPs) to actively target vulnerable plaques, halt localized ferroptosis, and systemically reprogram lipid metabolism. Methods Polymeric poly(lactic-co-glycolic acid) cores loaded with curcumin were cloaked with RAW264.7 macrophage-derived cell membranes via co-extrusion. in vitro cellular targeting, lipid handling, and anti-ferroptotic mechanisms were evaluated using oxidized LDL (ox-LDL)-stimulated macrophages. in vivo pharmacokinetic stability, homotypic plaque targeting, and therapeutic efficacy were comprehensively assessed in high-fat diet (HFD)-fed ApoE-/- mice. Furthermore, untargeted serum lipidomics were utilized to evaluate systemic metabolic reprogramming. Results Cum@MM-NPs exhibited a definitive core-shell architecture, successfully retained characteristic macrophage surface antigens, and demonstrated sustained curcumin release. in vitro , the biomimetic coating facilitated homotypic targeting to foam cells while rescuing them from ox-LDL-induced ferroptosis by chelating labile iron (Fe 2+ ), restoring GPX4 antioxidant defenses, and preventing pathological lipid droplet accumulation. in vivo , Cum@MM-NPs exhibited prolonged circulation and highly specific accumulation in aortic plaques. Therapeutically, Cum@MM-NP administration drastically reduced aortic plaque burden, inhibited local pro-inflammatory cytokine secretion, and stabilized vulnerable lesions by enhancing collagen-rich fibrous caps. Mechanistically, Cum@MM-NPs successfully arrested intraplaque ferroptosis, evidenced by normalized mitochondrial ultrastructure and cleared lipid peroxides (4-HNE). Beyond localized plaque stabilization, untargeted lipidomics revealed that the nanotherapy comprehensively reversed HFD-induced hepatic steatosis and systemically depleted circulating pro-ferroptotic polyunsaturated phosphatidylethanolamines (PE-PUFAs). Conclusions Cum@MM-NPs function as a highly biocompatible, dual-action nanotherapeutic platform. By simultaneously quenching localized vascular ferroptosis and systematically dismantling the pro-ferroptotic lipidome, this macrophage-biomimetic strategy offers a highly translatable paradigm for the treatment of advanced atherosclerosis and interconnected metabolic comorbidities.