Neural stem cell-derived small extracellular vesicles: a new therapy approach in neurological diseases

Mengyao Wang ^1,2 Dongdong Chen ^1,2 Renjie Pan ^1,2 Yue Sun ^1,2 Xinyu He ^1,2 Youming Qiu ^1,3 Yuexin Hu ^1,2 Xiangsheng Wu ^1,2 Xuxiang Xi ^1,2 Rong Hu ^1,2* Zhigang Jiao ^1,4,5,6*

• ¹ Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
• ² College of Medical Technology, Gannan Medical University, Ganzhou, China
• ³ The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
• ⁴ College of Medical Technology,The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
• ⁵ Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Gan zhou, China
• ⁶ Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi Province, China

Neural stem cells (NSCs) possess pluripotent characteristics, proliferative capacity, and the ability to self-renew. In the context of neurological diseases, transplantation of NSCs has been shown to facilitate neurological repair through paracrine mechanisms. NSC-derived small extracellular vesicles (NSC-sEVs), a prominent component of the NSC secretome, play a crucial role in modulating various physiological and pathological processes, such as regulating the NSC microenvironment, promoting endogenous NSC differentiation, and facilitating the maturation of neurons and glial cells. Moreover, NSC-sEVs exhibit reduced immunogenicity, decreased tumorigenic potential, and enhanced ability to traverse the blood-brain barrier. Consequently, NSC-sEVs present novel therapeutic approaches as non-cellular treatments for neurological disorders and are poised to serve as a viable alternative to stem cell therapies. Furthermore, NSC-sEVs can be manipulated to enhance production efficiency, improve biological activity, and optimize targeting specificity, thereby significantly advancing the utilization of NSC-sEVs in clinical settings for neurological conditions. This review provides a comprehensive overview of the biological functions of NSC-sEVs, their therapeutic implications and underlying molecular mechanisms in diverse neurological disorders, as well as the potential for engineering NSC-sEVs as drug delivery platforms. Additionally, the limitations and challenges faced by NSC-sEVs in practical applications were discussed in depth, and targeted solutions were proposed.