Neonatal small extracellular vesicle-loaded GelNB hydrogel reprograms the vascular-immune microenvironment for spinal cord injury repair.

Adult mammals with spinal cord injury (SCI) face permanent disability from failed regeneration and scarring, while neonatal mice achieve scarless repair. We show neonatal mouse circulating blood-derived small extracellular vesicles (NCE) rejuvenate adult spinal cord microvascular endothelial cells (SCMECs), restoring lipid metabolism, easing immune imbalance, and supporting neuroaxonal regrowth. Post-SCI myelin debris triggers IRS1-mediated PI3K-Akt-mTOR overactivation in SCMECs, causing harmful lipid droplet buildup, organelle dysfunction, and endothelial-to-mesenchymal transition (EndoMT). It also increases CXCL12 secretion from SCMECs, which recruits CXCR4+ macrophages. These macrophages release TNF-α and GDF15, promoting neuronal injury and EndoMT, and forming a destructive feedback loop. We create a "Microenvironment-Reprogramming Potent Hydrogel" - a high-adhesion GelNB hydrogel loaded with NCE - as an efficient delivery tool. NCE targetedly deliver miR-487b-3p to block IRS1 and CXCL12, breaking the vicious cycle. This remodels microvasculature, normalizes SCMEC lipid metabolism, reduces macrophage infiltration, promotes neuroregeneration, and achieves functional recovery. Our study uncovers an endothelium-immune crosstalk axis hindering SCI repair and highlights miR-487b-3p-rich sEVs as a promising therapy.