Zhihan Zhu,1,* Qiankun Zhang,1,* Jia Feng,1 Sonia Zebaze Dongmo,1 Qianqian Zhang,1 Songze Huang,1 Xiaowen Liu,1 Guilong Zhang,2 Lukui Chen1 

1Department of Neurosurgery, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Lukui Chen, Department of Neurosurgery, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, People’s Republic of China, Email neuro_clk@hotmail.com Guilong Zhang, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Email longshe05@sina.com

Abstract: Ischemic stroke, being a prominent contributor to global disability and mortality, lacks an efficacious therapeutic approach in current clinical settings. Neural stem cells (NSCs) are a type of stem cell that are only found inside the nervous system. These cells can differentiate into various kinds of cells, potentially regenerating or restoring neural networks within areas of the brain that have been destroyed. This review begins by providing an introduction to the existing therapeutic approaches for ischemic stroke, followed by an examination of the promise and limits associated with the utilization of NSCs for the treatment of ischemic stroke. Subsequently, a comprehensive overview was conducted to synthesize the existing literature on the underlying processes of neural stem cell-derived small extracellular vesicles (NSC-sEVs) transplantation therapy in the context of ischemic stroke. These mechanisms encompass neuroprotection, inflammatory response suppression, and endogenous nerve and vascular regeneration facilitation. Nevertheless, the clinical translation of NSC-sEVs is hindered by challenges such as inadequate targeting efficacy and insufficient content loading. In light of these limitations, we have compiled an overview of the advancements in utilizing modified NSC-sEVs for treating ischemic stroke based on current methods of extracellular vesicle modification. In conclusion, examining NSC-sEVs-based therapeutic approaches is anticipated to be prominent in both fundamental and applied investigations about ischemic stroke.

Keywords: neural stem cells, small extracellular vesicles, ischemic stroke, neuroprotection, neural regeneration