Puerarin-Loaded Macrophage-Derived Exosomes for Experimental Atherosclerosis

Atherosclerotic cardiovascular disease (AS) remains a leading global health concern. In this study, we investigated a macrophage-derived exosome-based delivery system for puerarin (Pue). The isolated vesicles were characterized by transmission electron microscopy, particle-size and zeta-potential analysis, and Western blot validation of extracellular vesicle-associated markers, including CD63, CD9, CD81, TSG101, and Alix, together with Calnexin as an endoplasmic-reticulum-associated negative/depletion marker. In vitro experiments showed that exosome-based delivery enhanced cellular uptake of puerarin and was associated with reduced oxidative-stress-related signals, decreased macrophage migratory activity, and reduced foam-cell-related readouts under the tested conditions. In vivo studies using an ApoE−/− mouse model showed that Pue–Exos reduced aortic plaque burden, promoted collagen deposition, and improved serum lipid-related indices. No obvious histopathological abnormalities were observed in major organs after treatment, suggesting preliminary in vivo tolerability. Mechanistic evaluation in C57BL/6 mice showed that treatment was associated with increased expression of HIF-1α, NF-κB, IL-6, IL-1β, CD68, and α-SMA under the present experimental conditions. Therefore, these findings are more appropriately interpreted as inflammation-associated signaling changes and remodeling-related responses, rather than definitive evidence of a uniformly suppressed inflammatory state or a confirmed anti-atherosclerotic mechanism. Taken together, these results suggest that macrophage-derived exosome-based delivery may improve the performance of puerarin in atherosclerosis-related experimental settings, although the underlying mechanism requires further clarification.