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Intranasal delivery of engineered extracellular vesicles promotes neurofunctional recovery in traumatic brain injury

Pengtao Li,Sishuai Sun,Xingyu Zhu,Xiaoyu Liu,R. Yin,Yihao Chen,Jianbo Chang,Liguo Ye,Jingxi Gao,Xiaoyan Zhao,Houshi Xu,Yue Wang,Wei Zuo,Zhao Sun,Shihua Wang,Xiao Zhang,Junji Wei,Robert Chunhua Zhao,Qin Han

Published 2025 in Journal of Nanobiotechnology

ABSTRACT

Traumatic brain injury (TBI) is a leading cause of disability in adults, significantly affecting patients’ quality of life. Extracellular vesicles (EVs) derived from human adipose-derived mesenchymal stem cells (hADSCs) have demonstrated therapeutic potential in TBI treatment. However, their limited targeting ability, short half-life, and low bioavailability present significant challenges for clinical application. In this study, we engineered extracellular vesicles (EEVs) by transfecting hADSCs with lentivirus and incorporating ultra-small paramagnetic nanoparticles (USPNs), resulting in EVs with enhanced miRNA expression and targeted delivery capabilities. These EEVs were administered intranasally to specifically target injury sites, effectively modulating the NF-κB signaling pathway to suppress neuroinflammation. In both in vitro and in vivo assessments, EEVs exhibited superior efficacy in promoting neurofunctional recovery and neurogenesis after brain injury compared to unmodified EVs. Furthermore, validation using human brain organoid models confirmed EEVs’ remarkable ability to suppress neuroinflammation, offering a promising strategy for TBI treatment.

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