Intranasal Mesenchymal Stem Cell-derived Exosomes Loaded with Phosphatase and Tensin Homolog Small Interfering RNA Enables Functional Recovery after Complete Spinal Cord Injury

Complete spinal cord injury (SCI) is a debilitating disease which usually leads to permanent functional impairments, with various complications and limited spontaneous recovery. Current investigation of molecular mechanisms controlling axon regeneration, (e.g., signaling networks and environmental cues), led to new strategies to enhance axonal regeneration. Here, we report that intranasal administrations of MSC-derived exosomes could penetrate the blood brain barrier, home selectively to spinal cord lesion, and show affinity to neurons within the lesion. Furthermore, in rats with complete SCI, intranasal administrations of MSC-exosomes loaded with phosphatase and tensin homolog small interfering RNA (PTEN-siRNA) silenced PTEN protein expression in the lesion and promoted robust axonal regeneration and angiogenesis, companied with decreased astrogliosis and microgliosis. Moreover, the intranasal PTEN-siRNA-loaded MSC-exosome treatment partially restored electrophysiological and structural integrity, and, most importantly, enabled remarkable functional recovery and significantly improved their movements. This rapid, non-invasive approach, using cell-free nano-swimmers carrying molecules to target pathophysiological mechanisms suggest novel strategy for clinical translation to SCI and beyond.