2. Academic Validation
  3. Central Nervous System Targeting Nanovesicles for Trans-Barrier Delivery and Spinal Cord Injury Treatment

Central Nervous System Targeting Nanovesicles for Trans-Barrier Delivery and Spinal Cord Injury Treatment

  • ACS Nano. 2025 Dec 19. doi: 10.1021/acsnano.5c08255.
Jingkai Wang 1 2 3 4 5,  Jiangjie Chen 1,  Jinyang Chen 1,  Kaishun Xia 1 2 3 4 5,  Pengcheng Yuan 6,  Xiaopeng Zhou 1 2 3 4 5,  Ronghao Wang 1,  Chao Yu 1 2 3 4 5,  Yi Li 1,  Kesi Shi 1,  Yuang Zhang 1 2 3 4 5,  Haibin Xu 1 2 3 4 5,  Tengfei Zhao 1 2 3 4 5,  Hao Li 1 2 3 4 5,  Qixin Chen 1 2 3 4 5,  Shiqing Feng 7 8,  Chengzhen Liang 1 2 3 4 5
Affiliations

Affiliations

  • 1 Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, PR China.
  • 2 Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang 310009, PR China.
  • 3 Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province 310009, PR China.
  • 4 Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province 310009, PR China.PR China.
  • 5 State Key Laboratory of Transvascular lmplantation Devices, Hangzhou 310009, China.
  • 6 College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, China.
  • 7 The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China.
  • 8 Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China.
PMID: 41420148 DOI: 10.1021/acsnano.5c08255
Abstract

The central nervous system (CNS) barrier obstructs therapeutic component entrance and hinders the therapy efficiency of CNS diseases. An ideal delivery system should penetrate and concentrate in the CNS without safety concerns. Nanovesicles (NVs) are a popular delivery tool, because of their biological homology, inherent homing effects, and capacity to penetrate barriers. However, the delivery efficacy of NVs is insufficient for CNS disease therapy, and the mechanism for barrier penetration remains elusive. Herein, nanovesicles (NVs) were extruded from mesenchymal stem cells and modified by a lesion tissue affinity peptide (CAQK) for spinal cord injury (SCI) therapy. The NVs penetrated endothelial barriers effectively in vitro. Subsequently, the CNS barrier penetration capacity of the CAQK-conjugated NVs (CNVs) was verified in vivo in spinal cord injury (SCI) and the temporary middle cerebral artery occlusion (t-MCAO) mouse models. Furthermore, the endothelial barrier penetration of CNVs depended on the active endocytosis by endothelial cells. After endocytosis, the Rab11+ endosome was identified to mediate a transcellular transcytosis to transport CNVs across the barrier. In the SCI model, CNVs promoted the lesion tissue accumulation, leading to improvement in the neural functional recovery. In summary, we developed a natural NV tool for SCI therapy, employing the inherent CNS barrier penetration capacity and enhanced lesion tissue homing characteristics of NVs. The NVs crossed the CNS barriers via active endocytosis, followed by Rab11+ endosome-mediated transcytosis. The CNV exhibited good delivery efficacy and therapeutic effects in CNS diseases and has the potential for clinical translation.

Keywords

central nervous system; endothelial barrier; nanovesicle; tissue targeting delivery; transcytosis.

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