Intranasal Delivery of Brain‐Derived Neurotrophic Factor (BDNF)‐Loaded Small Extracellular Vesicles for Treating Acute Spinal Cord Injury in Rats and Monkeys

作者：Zhonghai Huang, Jing Li, Jin Wo, Chenglin Li, Zi‐Cong Wu, Xiaohui Deng, Yaying Liang, Fuxiang Li, Boli Chen, Bin Jia, Lu Wang, Ying Wang, Guodong Sun, Zhizhong Li, Hui Zhu, James D. Guest, Kwok‐Fai So, Qing‐Ling Fu, Libing Zhou · 发表于：Journal of Extracellular Vesicles · 年份：2025 · DOI：10.1002/jev2.70066 · 被引用次数：33 · 研究领域：Extracellular vesicles in disease、Spinal Cord Injury Research、Spinal Dysraphism and Malformations

Besides surgical decompression, neuroprotection and neuroinflammation reduction are critical for acute spinal cord injury (SCI). In this study, we prepared small extracellular vesicles (sEVs) from immortalised mesenchymal stem cells overexpressing brain-derived neurotrophic factor (BDNF) and evaluated whether intranasal administration of BDNF-sEVs is a therapeutic option for acute SCI. In cultured neurons, BDNF loading enhanced neurite outgrowth promoted by sEVs. After intranasal administration, mCherry-labelled 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-sEVs 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-sEV treatment showed improved neural repair and functional recovery compared to those with sEV treatment. Intranasal administration of BDNF-sEVs, but not of sEVs, increased BDNF levels and phosphorylation of downstream signals in the rat-injured spinal cord samples, indicating activation of the BDNF/TrkB signalling pathway. In acute SCI monkeys, intranasal administration of BDNF-sEVs was further confirmed to inhibit glial reactivities and proinflammatory cytokine release, increasing BDNF levels in the cerebrospinal fluid, enhancing...