Adipose-derived stem cell exosomes (ADSC-exos) are promising for nerve regeneration
however, their precise mechanisms remain unclear. This study employed fluorescent labeling and spatial transcriptomics to track the effects of ADSC-exos on crushed sciatic nerves in mice. Labeled exosomes were detected in spinal neurons and proximal nerve segments after application. Spatial transcriptomics revealed significant changes in gene expression, with an upregulation of neurons and Schwann cells and the downregulation of oligodendrocytes. The key pathways affected were prosaposin, pleiotrophin, fibroblast growth factor, secreted phosphoprotein 1, SLIT and NTRK-like family, member, vascular endothelial growth factor, and growth arrest-specific protein. ADSC-exo treatment enhanced cell-cell interactions, particularly between Schwann cells and astrocytes, thereby promoting a regenerative environment. Gene ontology analysis suggested improvements in metabolic activity, cell communication, and structural support. This study highlights the complex interplay between multiple cell types and signaling pathways involved in the nerve regeneration response to ADSC-exos. This comprehensive approach offers new perspectives on the role of ADSC-exos in nerve regeneration and paves the way for advanced regenerative strategies for peripheral nerve injuries.