Pitavastatin-loaded procyanidins self-assembled nanoparticles alleviate advanced atherosclerosis via modulating macrophage efferocytosis and cholesterol efflux

Advanced atherosclerosis is the major global cause of death, as featured by the aggregation of apoptotic cells (ACs) in necrotic cores. The defective efferocytosis and dysfunctional cholesterol efflux of macrophages are the main reasons for forming necrotic cores in advanced atherosclerosis. In this study, we constructed self-assembled procyanidins (PC) NPs for loading pitavastatin (Pita). The designed HA@PC@Pita NPs with hyaluronic acid (HA) modification combined the advantages of efferocytosis restoration of Pita and cholesterol efflux enhancement of PC. <i>In vitro</i> assay indicated that HA@PC@Pita NPs could induce M1/M2 repolarization and upregulate ERK5/Mertk expression to restore efferocytosis of macrophages. Simultaneously, HA@PC@Pita NPs notably promoted cholesterol efflux by promoting macrophage lipophagy, a selective autophagy of lipid droplets. <i>In vivo</i> study showed that HA@PC@Pita NPs cleared necrotic core and enhanced plaque stability in the <i>ApoE</i> ^<i>-/-</i> mice model with advanced atherosclerosis. Taken together, this study demonstrated the potential of HA@PC@Pita NPs for the treatment of advanced atherosclerosis.