Engineered extracellular vesicles from human placental mesenchymal stem cells attenuate abdominal aortic aneurysm formation by inhibiting Nat10-mediated vascular smooth muscle cell senescence.

Human placental mesenchymal stem cell-derived extracellular vesicles (hPMSC-EVs) have demonstrated anti-senescence effects across various diseases. However, their role in abdominal aortic aneurysm (AAA), a degenerative aortic pathology, remains unexplored. Our findings demonstrated that hPMSC-EVs effectively delay vascular smooth muscle cell (VSMC) senescence. In vivo, modification of hPMSC-EVs with an osteopontin(OPN)-targeted peptide facilitated precise homing to aneurysmal sites and improved local retention. Additionally, administration of OPN-targeted hPMSC-EVs significantly reduced AAA formation in both AngII and elastase-induced murine models, by inhibiting VSMC senescence. Mechanistic studies further demonstrated that hPMSC-EVs suppressed VSMC senescence and lowered AAA incidence through downregulation of Nat10 expression. MiRNA sequencing identified miR-149-5p encapsulated in hPMSC-EVs as the key mediator of Nat10 suppression. These results position OPN-targeted hPMSC-EVs as a promising targeted therapy for AAA, exerting protective effects via the miR-149-5p/Nat10/senescence axis.