Precisely targeting of engineered nanovesicles to implanted scaffolds via click chemistry for microenvironment regulation in acute spinal cord injury

  • J Control Release. 2025 Oct 14;388(Pt 1):114321. doi: 10.1016/j.jconrel.2025.114321.
Xunqi Zhang  1 ,  Manning Zhu  1 ,  Jing Guo  1 ,  Jian Cao  1 ,  Juanjuan Zheng  1 ,  Jiahe Wu  2 ,  Weihang Zhou  1 ,  Xinchi Jiang  1 ,  Nan Wang  3 ,  Jiafu Mu  1 ,  Tianchen Huang  1 ,  Jian-Qing Gao  4
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2. Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China.
  • 3. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China.
  • 4. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou 310058, China; Jinhua Institute of Zhejiang University, Jinhua 321002, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China; Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. Electronic address: [email protected].
PMID: 41101695 DOI: 10.1016/j.jconrel.2025.114321
Abstract

Spinal cord injury (SCI) requires sufficient and sustained therapeutic intervention for microenvironment regulation in the acute phase. However, systemic drug administration is often ineffective due to non-specific distribution within the damaged spinal cord. While local implantation systems have gained attention for site-specific delivery, they are often constrained by spatial limitations and present challenges in designing sequential release profiles. Herein, we report the development of a composite drug delivery system integrating intranasal administration with local implantation. Specifically, the locally implanted scaffold was modified with dibenzocyclooctyne (DBCO) groups (dGN). Azide group-functionalized nanovesicles (aNVs), extruded from engineered mesenchymal stem cells, were continuously administered intranasally. aNVs accumulated within the lesion by undergoing a bio-orthogonal click chemistry reaction with dGN, which markedly enhanced their local distribution and retention. The composite drug delivery system, dGN&aNVs, effectively promoted acute microenvironmental regulation, hindlimb motor function recovery, associated symptoms alleviation, and tissue repair and regeneration following SCI in rats. This work presents a robust and minimally invasive platform for the precision-targeted therapy of SCI.

Keywords
Click chemistry; Composite drug delivery system; Intranasal administration; Local implantation system; MSCs-extruded nanovesicles; Spinal cord injury.
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