Engineered BMSC-derived exosomes deliver miR-17-5p inhibitor to restore sensory conduction via the...

Spinal cord dorsal column lesions (SDCL) disrupt sensory conduction, with no effective clinical treatments available. The miR-17-5p inhibitor and exosomes (EXOs) derived from bone marrow mesenchymal stem cells (BMSCs) have potential for promoting nerve regeneration. This study aims to engineer BMSC-derived exosomes to deliver the miR-17-5p inhibitor, synergistically enhancing axonal regeneration, restoring sensory processing in an SDCL rat model, and elucidating mechanisms. Bioinformatics analysis was used to identify critical pathways associated with the neuroregenerative effects of EXOs. The delivery efficiency of EXOs was assessed by RT-qPCR. Immunofluorescence was used to evaluate EXO internalization and axonal regeneration potential. Key proteins were validated via western blotting and ELISA. Immunohistochemistry and the Tape Removal Test were utilized to evaluate the efficacy of neural injury repair. Transcriptomic (p.adjust = 0.003) and miRNomic (p.adjust = 0.0008) analyses suggest that the JAK/STAT pathway may play a pivotal role in the neuroregenerative effects of EXOs. Following the repair efficacy validation of both the miR-17-5p inhibitor and BMSC-derived EXOs, EXOs carrying the miR-17-5p inhibitor more effectively enhance DRG neuron axonal outgrowth (309.36 ± 24.63 μm; p < 0.0001) and restore sensory conduction in SDCL rats (%Area positive = 78.59 ± 8.20 %; p < 0.0001) through the IL-11/GP130/STAT3/GAP-43 axis. BMSC-derived EXOs loaded with the miR-17-5p inhibitor synergistically promote axonal growth and restore sensory conduction in SDCL rats through the IL-11/GP130/STAT3/GAP-43 axis. This study integrates the intrinsic reparative properties of BMSC-derived EXOs with their unique advantages as nanoscale carriers for miR-17-5p inhibitor delivery, demonstrating therapeutic potential in overcoming the limited intrinsic regenerative capacity of neurons in adult mammals.