VAP peptide-modified Forsythiaside A-pretreated exosomes promote the repair of the blood-spinal cord barrier by regulating endothelial cell autophagy

FSA-pretreated Huc-MSCs generate potent exosomes to promote BSCB repair via TJs. • VAP peptide targets FSA-Exos to SCI endothelium via GRP78 for precise repair. • VAP-Exos promote BSCB repair by regulating endothelial cell autophagy. Spinal cord injury (SCI) disrupts the blood-spinal cord barrier (BSCB), triggering secondary damage and permanent neurological deficits. Forsythiaside A is a natural bioactive compound isolated from Forsythia suspensa. It boasts robust anti-inflammatory and tissue-repairing capacities and can precondition stem cells to enhance the therapeutic potency of their secreted exosomes. To equip FSA-primed exosomes with precise targeting, we utilized SNTRVAP (VAP), a GRP78-specific peptide with the sequence SNTRVAP. Here, we constructed VAP-Exos by conjugating VAP onto FSA-preconditioned human umbilical cord mesenchymal stem cell exosomes, which effectively restore BSCB integrity. Binding GRP78 to target endothelial cells, VAP-Exos upregulates tight junction proteins (ZO-1, Occludin, Claudin5) and lowers BSCB permeability. Single-nucleus sequencing proves they stimulate endothelial proliferation, elevate Itga5, and activate autophagy pathways; elevated autophagic flux is validated by increased LC3-II/I ratio and P62 degradation. Meanwhile, VAP-Exos alleviate oxidative stress, shift microglia toward the anti-inflammatory M2 phenotype, and rebalance the spinal immune microenvironment. In vivo assays on SCI mice show smaller lesions, attenuated glial scarring and recovered motor function. Collectively, VAP-Exos safeguard BSCB integrity through endothelial autophagy modulation, representing a promising engineered exosome candidate for SCI therapy. Download: Download high-res image (184KB) Download: Download full-size image