Atherosclerosis (AS) is closely linked to endothelial cell (EC) senescence and mitochondrial dysfunction, which impair vascular repair. Resveratrol (RSV) has antioxidant, anti-inflammatory, and pro-angiogenic effects, but its clinical use is restricted by poor bioavailability. This study aimed to construct a platelet membrane-coated resveratrol nanosystem (PM@RSV NPs) and investigate its mechanism of action in delaying the progression of AS by activating FOXM1 to improve mitochondrial function, inhibit EC senescence, and promote vascular regeneration. PM@RSV NPs were prepared using a solvent evaporation method combined with membrane-coating technology, and gene expression profiles and key regulatory networks were analyzed through RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), and least absolute shrinkage and selection operator (LASSO) regression. In vitro, PM@RSV NPs enhanced mitochondrial membrane potential and ATP generation while decreasing ROS accumulation and the number of SA-β-Gal-positive cells, accompanied by FOXM1 upregulation in ECs. In vivo experiments demonstrated that PM@RSV NPs significantly reduced plaque area, improved mitochondrial function, decreased levels of senescence markers, and promoted vascular regeneration via FOXM1 regulation. In addition, PM@RSV NPs preferentially accumulated in ox-LDL-injured MAECs and AS lesion-associated vascular endothelium, mainly through platelet-membrane adhesion proteins such as GPV and P-selectin; their biosafety was evaluated by EC viability/apoptosis assays, histological examination of major organs, and serum biochemical indices of liver and kidney function. This study confirmed that PM@RSV NPs improved mitochondrial function, inhibited endothelial senescence, and enhanced vascular regeneration by activating FOXM1, offering a novel therapeutic strategy for treating AS.
