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Central Nervous System Targeting Nanovesicles for Trans-Barrier Delivery and Spinal Cord Injury Treatment
Jingkai Wang1,2,3,4,5, Jiangjie Chen1, Jinyang Chen1
1Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, PR China.
ACS Nano
|December 19, 2025
Summary
This study developed CAQK-conjugated nanovesicles (CNVs) from mesenchymal stem cells to overcome central nervous system (CNS) barriers for spinal cord injury (SCI) therapy. CNVs enhance drug delivery and improve neural functional recovery in CNS disease models.
Area of Science:
- Biotechnology and Nanomedicine
- Neuroscience and Neurodegenerative Diseases
- Regenerative Medicine
Background:
- The central nervous system (CNS) barrier poses a significant challenge to treating CNS diseases, limiting therapeutic agent delivery and efficacy.
- Existing nanovesicles (NVs) show promise for CNS delivery due to their biological compatibility but often lack sufficient penetration and targeting capabilities.
- The precise mechanisms by which NVs cross the CNS barrier remain incompletely understood, hindering optimization for therapeutic applications.
Purpose of the Study:
- To develop and evaluate enhanced nanovesicles (NVs) for improved therapeutic delivery across the CNS barrier.
- To investigate the mechanism of CNS barrier penetration mediated by modified NVs.
- To assess the therapeutic efficacy of these NVs in preclinical models of CNS injury, specifically spinal cord injury (SCI).
Main Methods:
- Mesenchymal stem cell-derived nanovesicles (NVs) were engineered and conjugated with a lesion tissue affinity peptide (CAQK) to create CAQK-conjugated NVs (CNVs).
- NV and CNV penetration across endothelial barriers was assessed *in vitro* and *in vivo* using spinal cord injury (SCI) and transient middle cerebral artery occlusion (t-MCAO) mouse models.
- The cellular mechanisms of CNV transport across the endothelial barrier, including endocytosis and transcytosis pathways, were elucidated.
Main Results:
- CNVs demonstrated effective penetration of endothelial barriers *in vitro* and *in vivo* in CNS injury models.
- Endothelial barrier penetration of CNVs was mediated by active endocytosis, followed by Rab11+ endosome-dependent transcellular transcytosis.
- In the SCI model, CNVs exhibited enhanced accumulation at the lesion site, leading to significant improvements in neural functional recovery.
Conclusions:
- A novel nanovesicle (NV) delivery system (CNVs) was successfully developed for CNS disease therapy, particularly for spinal cord injury (SCI).
- CNVs effectively cross the CNS barrier via active endocytosis and Rab11+ endosome-mediated transcytosis, enhancing lesion targeting.
- The developed CNVs show significant therapeutic potential for CNS diseases, with promising prospects for clinical translation.
