Membrane-camouflaged liposomes Co-delivering L-Arg and NMN for reprogramming macrophage nitric oxide metabolism in atherosclerosis

Atherosclerosis progression is closely linked to metabolic dysfunction of plaque macrophages, where inducible nitric oxide synthase (iNOS)-mediated pathological nitric oxide (NO) burst is a key driver of inflammation and oxidative stress. This study designed macrophage membrane-camouflaged liposomes (M-AN@Lip) for the co-delivery of nicotinamide mononucleotide (NMN) and L-arginine (L-Arg), aiming to precisely regulate macrophage NO metabolic homeostasis. In vitro experiments demonstrated that M-AN@Lip effectively increased intracellular NO generation while significantly downregulating the expression of the oxidative stress-related enzyme NAD(P)H quinone oxidoreductase 1 (NQO1), suggesting a reprogramming of macrophage NO metabolism from a pathological iNOS-dominated pathway towards a protective one. This metabolic shift was accompanied by clearance of intracellular reactive oxygen species (ROS), enhancement of the endogenous antioxidant enzyme system, and polarization of macrophages towards an anti-inflammatory M2 phenotype. Ultimately, M-AN@Lip significantly inhibited oxidized low-density lipoprotein (ox-LDL) uptake and foam cell formation by downregulating the expression of scavenger receptors (CD36, MSR1, SRB1). This study demonstrates that a biomimetic nano-system can achieve integrated anti-inflammatory, antioxidant, and anti-foam cell forming effects through the synergistic regulation of NO metabolism, offering a promising novel nanotherapeutic strategy for atherosclerosis.