Pitavastatin and resveratrol bio-nanocomplexes against hyperhomocysteinemia-induced atherosclerosis via blocking ferroptosis-related lipid deposition

Atherosclerosis (AS) therapy has been commonly based on lipid-lowering agents ( e.g. , statins), supplemented by other therapies, such as anti-inflammatory agents and antioxidants, through traditional Chinese herbs. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has been implicated in the progression of AS, particularly in macrophages. In the study, we constructed a macrophage targeted hybridization nanodrug of HMLRPP NPs, which used Pit-loaded Poly(lactic- co -glycolic) acid (PLGA) nanoparticles and Res-loaded liposomes (Lipo) as nano-core, then, coated with a macrophage membrane hybridized by hyaluronic acid (HA). The nanodrug prolonged blood circulation time and achieved optimal Res and Pit accumulation in the atherosclerotic plaques by effectively evading immune system clearance. In vivo studies demonstrated that HMLRPP NPs significantly attenuated plaque progression, characterized by decreased plaque area, less lipid deposition, and increased collagen. Meanwhile, HMLRPP NPs inhibited macrophage ferroptosis by decreasing the expression of β-Hydroxybutyrate dehydrogenase 1 (BDH1), Orosomucoid 1 (ORM1) and enhancing the expression of Ribosomal protein S27-like (RPS27L), which resulted in the alleviation of lipid accumulation and inflammation. Our data suggest that the HMLRPP nanodrug delivery system with ferroptosis-regulating capability provides a feasible therapeutic strategy for atherosclerosis.