Endothelialized human umbilical cord mesenchymal stem cell-derived exosomes enhances angiogenesis and stabilizes the blood-spinal cord barrier after spinal cord injury.

Restoration of vascular structure and function is pivotal for neurological recovery following spinal cord injury (SCI), yet repairing the blood-spinal cord barrier (BSCB) remains a significant challenge. In this study, we demonstrate that exosomes (Exos) derived from endothelialized human umbilical cord mesenchymal stem cells (E‑UCMSCs) markedly enhance angiogenesis, improve vascular function, and promote neurological recovery. Human umbilical cord mesenchymal stem cells were induced to differentiate into endothelial‑like cells, and RNA‑sequencing revealed upregulation of genes associated with angiogenesis and vascular barrier integrity, alongside activation of relevant signaling pathways. In a co‑culture system, E‑UCMSC‑derived Exos significantly enhanced bEnd.3 cell migration and BSCB stability. To enable targeted delivery to neovasculature, Exos were engineered with RGD peptides (RGD‑E‑UCMSC‑Exos) via lentiviral modification. In vivo, these modified Exos preferentially localized to neovascular endothelial cells, promoted angiogenesis, reinforced BSCB integrity, and improved neurological outcomes in SCI mouse models. Proteomic profiling identified key angiogenic and barrier‑stabilizing factors carried by RGD‑E‑UCMSC‑Exos, including MMP2, FLT1, TIMP1, GAS6, CTHRC1, and NEO1, which likely mediate their therapeutic effects. Collectively, these findings provide novel mechanistic insights and establish a novel strong preclinical foundation for exosome‑based therapies in SCI.