Complete spinal cord injury (SCI) is a debilitating disease which usually leads to permanent functional impairments, with various complications and limited spontaneous recovery or efficient treatment. Here, we report that in rats with complete SCI, intranasal administrations of mesenchymal stem cells-derived exosomes (MSC-Exo) could penetrate the blood brain barrier, home selectively to the spinal cord lesion, and show affinity to neurons within the lesion. When these exosomes were loaded with phosphatase and tensin homolog small interfering RNA, termed ExoPTEN, they migrated from the nose and silenced PTEN expression in the lesion. Furthermore, the loaded exosomes promoted robust axonal regeneration and angiogenesis, accompanied with decreased astrogliosis and microgliosis. Moreover, the intranasal ExoPTEN treatment partially restored electrophysiological and structural integrity, and most importantly, enabled remarkable functional recovery. This rapid, non-invasive approach, using cell-free nano-swimmers carrying molecules to target pathophysiological mechanisms, suggests novel strategy for clinical translation to SCI and beyond.