Local delivery of mesenchymal stem cell-extruded nanovesicles through a bio-responsive scaffold for acute spinal cord injury treatment

  • Int J Pharm. 2025 Feb 25:671:125222. doi: 10.1016/j.ijpharm.2025.125222.
Xunqi Zhang  1 ,  Jian Cao  1 ,  Jiahe Wu  2 ,  Jiafu Mu  1 ,  Tianchen Huang  1 ,  Juanjuan Zheng  1 ,  Jing Guo  1 ,  Manning Zhu  1 ,  Shiqing Feng  3 ,  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. International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, 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: 39814243 DOI: 10.1016/j.ijpharm.2025.125222
Abstract

Intense inflammatory responses and elevated levels of Reactive Oxygen Species (ROS) extremely exacerbate the pathological process of spinal cord injury (SCI). Mesenchymal stem cell (MSC)-derived extracellular vesicles (EV) can mitigate SCI-related inflammation but their production yield remains limited. Alternatively, MSC-extruded nanovesicles (NV) inherit the therapeutic potential from MSCs and have a markedly higher yield than EV. In the present study, a bio-responsive scaffold system (RS+NV) was created for SCI treatment. NV was generated from human MSCs by physical extrusion and encapsulated in a ROS-responsive scaffold (RS). RS+NV efficiently scavenged environmental ROS and underwent degradation, thus facilitating the responsive release of NV. NV inhibited the pro-inflammatory phenotypic transformation, and reduced the secretion of TNF-α and IL-6 from lipopolysaccharide-stimulated BV2 cells, exhibiting comparable anti-inflammatory properties to EV. Additionally, NV posed a superior antioxidative effect than EV and could effectively alleviate the oxidative stress damage of H2O2-stimulated PC12 cells. Furthermore, in SCI rats, the uptake of NV was primarily attributed to microglia and neurons. RS+NV exhibited synergistic effects in regulating the hostile microenvironment in vivo during the acute phase, thereby establishing a conducive environment for long-term locomotor, tissue repair, and recovery of neuropathic pain. Overall, RS+NV shows promising potential for use as an anti-inflammatory and antioxidative therapeutic approach for treating SCI.

Keywords
Bioactive materials; Extracellular vesicles; Extruded nanovesicles; Mesenchymal stem cells; Spinal cord injury.
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