Click chemistry extracellular vesicle/peptide/chemokine nanocarriers for treating central nervous system injuries

Huitong Ruan; Yongfang Li; Cheng Wang; Yixu Jiang; Yulong Han; Yiwei Li; Dandan Zheng; Jing Ye; Gang Chen; Guo-Yuan Yang; Lianfu Deng; Ming Guo; Xingcai Zhang; Yaohui Tang; Wenguo Cui

doi:10.1016/j.apsb.2022.06.007

Click chemistry extracellular vesicle/peptide/chemokine nanocarriers for treating central nervous system injuries

Acta Pharm Sin B. 2023 May;13(5):2202-2218. doi: 10.1016/j.apsb.2022.06.007. Epub 2022 Jun 10.

Authors

Huitong Ruan^{1

2}, Yongfang Li³, Cheng Wang⁴, Yixu Jiang⁴, Yulong Han^{5

6}, Yiwei Li^{5

6}, Dandan Zheng¹, Jing Ye⁴, Gang Chen², Guo-Yuan Yang⁴, Lianfu Deng¹, Ming Guo⁵, Xingcai Zhang⁶, Yaohui Tang⁴, Wenguo Cui¹

Affiliations

¹ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Jiaxing Key Laboratory of Basic Research and Clinical Translation on Orthopedic Biomaterials, Department of Orthopaedics, the Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China.
³ Department of Rehabilitation Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
⁴ Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
⁵ School of Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.

Abstract

Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are essential causes of death and long-term disability and are difficult to cure, mainly due to the limited neuron regeneration and the glial scar formation. Herein, we apply extracellular vesicles (EVs) secreted by M2 microglia to improve the differentiation of neural stem cells (NSCs) at the injured site, and simultaneously modify them with the injured vascular targeting peptide (DA7R) and the stem cell recruiting factor (SDF-1) on their surface via copper-free click chemistry to recruit NSCs, inducing their neuronal differentiation, and serving as the nanocarriers at the injured site (Dual-EV). Results prove that the Dual-EV could target human umbilical vascular endothelial cells (HUVECs), recruit NSCs, and promote the neuronal differentiation of NSCs in vitro. Furthermore, 10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis, and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs, miR30b-3p, miR-222-3p, miR-129-5p, and miR-155-5p may exert effect of inducing NSC to differentiate into neurons. In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice, potentiate NSCs recruitment, and increase neurogenesis. This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells, and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.

Keywords: Central nervous system injuries; Click chemistry; Extracellular vesicles; Microglia; Neural stem cell; Neurogenesis; Stroke; Targeted delivery.