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In this study, we prepared small extracellular vesicles (sEVs) from immortalised mesenchymal stem cells overexpressing brain\u2010derived neurotrophic factor (BDNF) and evaluated whether intranasal administration of BDNF\u2010sEVs is a therapeutic option for acute SCI. In cultured neurons, BDNF loading enhanced neurite outgrowth promoted by sEVs. After intranasal administration, mCherry\u2010labelled sEVs were transported to the injured spinal cords of rats and monkeys and mainly taken up by neurons. In acute SCI rats, intranasal administration of sEVs and BDNF\u2010sEVs reduced glial responses and proinflammatory cytokine production, enhanced neuronal survival and angiogenesis in the lesion, promoted injured axon rewiring, delayed lumbar spinal motoneuron atrophy below the lesion, and improved functional performance. The rats receiving BDNF\u2010sEV treatment showed improved neural repair and functional recovery compared to those with sEV treatment. Intranasal administration of BDNF\u2010sEVs, but not of sEVs, increased BDNF levels and phosphorylation of downstream signals in the rat\u2010injured spinal cord samples, indicating activation of the BDNF\/TrkB signalling pathway. In acute SCI monkeys, intranasal administration of BDNF\u2010sEVs was further confirmed to inhibit glial reactivities and proinflammatory cytokine release, increasing BDNF levels in the cerebrospinal fluid, enhancing neural network rewiring of injured spinal cords and neuronal activities of the brain, and improving functional performances in behavioural tests and electrophysiological recordings. In conclusion, BDNF\u2010sEVs play a combinatory therapeutic role of sEVs and BDNF, and intranasal administration of BDNF\u2010sEVs is a potential option for the clinical treatment of acute SCI.<\/jats:p>","DOI":"10.1002\/jev2.70066","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T23:44:49Z","timestamp":1744069489000},"source":"Crossref","is-referenced-by-count":44,"title":["Intranasal Delivery of Brain\u2010Derived Neurotrophic Factor (BDNF)\u2010Loaded Small Extracellular Vesicles for Treating Acute Spinal Cord Injury in Rats and Monkeys"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8249-6297","authenticated-orcid":false,"given":"Zhonghai","family":"Huang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital) Jinan University  Heyuan 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