<p>This study investigates the role of salidroside-pretreated small extracellular vesicles (SAL-sEVs) derived from human umbilical cord mesenchymal stem cells (Huc-MSCs) in spinal cord injury (SCI). Results demonstrate that these sEVs repair the damaged blood-spinal cord barrier (BSCB) and facilitate functional recovery. sEVs were collected from Huc-MSCs pretreated with salidroside via ultracentrifugation. sEVs were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The uptake of sEVs by endothelial cells was confirmed through immunofluorescence. The regulatory effects of SAL-sEVs on BSCB permeability and tight junction proteins were examined using immunofluorescence and Western blot. Microglial polarization was assessed via ELISA, qRT-PCR, and Western blot. Motor function was evaluated through behavioral tests. SAL-sEVs were endocytosed by endothelial cells, reduced BSCB permeability by regulating tight junction proteins, alleviated secondary inflammation, facilitated repair of spinal cord injury sites, and improved motor function in mice. Salidroside augments the therapeutic promise of Huc-MSC-derived small extracellular vesicles in repairing the BSCB, inflammation reduction, and functional recovery post-SCI, offering a novel therapeutic approach for the treatment of SCI.</p> Graphical Abstract <p></p>