Targeted restoration of macrophage mitochondrial function by astaxanthin-geniposide co-assembled nanosystem for atherosclerosis treatment

Atherosclerosis (AS) is characterized by chronic, persistent inflammation and lipid deposition. Macrophage mitochondrial dysfunction leads to excessive release of reactive oxygen species (ROS), exacerbating inflammatory responses and lipid metabolism dysfunction. This study developed a novel nanodrug system (TM@AG NPs) for restoring macrophage mitochondrial function. The system is based on the co-assembly of astaxanthin (AST) and geniposide (Gen), with macrophage membrane coating and triphenylphosphonium (TPP) modification. In vitro experiments demonstrated that mitochondria-targeted TM@AG NPs promoted the repolarization of macrophages from the M1 to the M2 phenotype and suppressed inflammation by efficiently scavenging mitochondrial ROS (mtROS), restoring mitochondrial respiration and energy supply, thereby ameliorating lipid metabolism disorders. In vivo assay using ApoE −/− mice model demonstrated that TM@AG NPs efficiently accumulated in atherosclerotic plaques, significantly reduced plaque area, cleared the necrotic core, and enhanced plaque stability. In summary, this study presents a sequentially targeted strategy for the precise treatment of AS.