Targeted delivery of CD163+ macrophage-derived small extracellular vesicles via RGD peptides promote vascular regeneration and stabilization after spinal cord injury.

Targeted delivery of small extracellular vesicles (sEVs) with low immunogenicity and fewer undesirable side effects are needed for spinal cord injury (SCI) therapy. Here, we show that RGD (Arg-Gly-Asp) peptide-decorated CD163+ macrophage-derived sEVs can deliver TGF-ß to the neovascular endothelial cells of the injured site and improve neurological function after SCI. CD163+ macrophages are M2 macrophages that express TGF-ß and are reported to promote angiogenesis and vascular stabilization in various diseases. Enriched TGF-ß EVs were crucial in angiogenesis and tissue repair. However, TGF-ß also boosts the formation of fibrous or glial scars, detrimental to neurological recovery. Our results found RGD-modified CD163+ sEVs accumulated in the injured region and were taken up by neovascular endothelial cells. Furthermore, RGD-CD163+ sEVs promoted vascular regeneration and stabilization in vitro and in vivo, resulting in substantial functional recovery post-SCI. These data suggest that RGD-CD163+ sEVs may be a potential strategy for treating SCI.