M1 macrophage-derived exosomal miR-155-5p exacerbates aortic dissection via SMAD5-Mediated regulation of vascular smooth muscle cell phenotype

Aortic dissection (AD) is a life-threatening cardiovascular emergency characterized by acute aortic wall injury and high mortality, yet effective pharmacological therapies remain limited. Macrophage infiltration and vascular smooth muscle cell (VSMC) phenotypic switching from contractile to synthetic states are central to AD pathogenesis, but the mechanisms mediating intercellular communication between macrophages and VSMCs are incompletely understood. Emerging evidence suggests that exosomes can transfer bioactive miRNAs between cells; however, whether M1 macrophage-derived exosomes promote AD progression through specific miRNA delivery and whether they can be engineered for therapeutic intervention have not been clearly defined. In this study, we demonstrate that M1 macrophage-derived exosomes deliver miR-155-5p to VSMCs, where it targets and suppresses SMAD5, activates the RHOA/ROCK pathway, and drives contractile-to-synthetic phenotypic switching, thereby accelerating AD progression. Through comprehensive physicochemical characterization, including TEM, NTA, Zeta potential, and stability assays, we show that M0 macrophage-derived exosomes can be successfully engineered to load Antago-miR-155-5p via electroporation with favorable encapsulation efficiency and colloidal stability. In a BAPN-induced mouse model of AD, intravenous administration of Antago-miR-155-5p-loaded M0-Exos significantly improved survival, reduced AD incidence and aortic dilation, and restored VSMC contractile markers. Biodistribution studies using DiR and CY5 labeling confirmed efficient accumulation of these engineered exosomes in the injured aorta, while macrophage depletion and rescue experiments validated the pathogenic role of M1-derived exosomes. These findings identify a novel M1 exosome-miR-155-5p-SMAD5/RHOA/ROCK signaling axis in AD and establish engineered M0 macrophage-derived exosomes as a promising bioactive material platform for targeted miRNA therapy in aortic dissection.