A Multidimensional Engineering Strategy Reprograms Microglia via Targeted and Sustained‐Release Extracellular Vesicles for Spinal Cord Injury Repair
5 affiliations
- 1Department of Orthopedics The First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu China
- 2Department of human anatomy School of Basic Medicine Nanjing Medical University Nanjing Jiangsu China
- 3Department of Orthopaedics Fourth Military Medical University Xi'an Shaanxi China
- 4Department of Orthopedics The Affiliated Taizhou People's Hospital of Nanjing Medical University Taizhou School of Clinical Medicine Nanjing Medical University Taizhou Jiangsu China
- 5Department of Pharmaceutics School of Pharmacy Nanjing Medical University Nanjing Jiangsu China
Abstract
Spinal cord injury (SCI) induces neuroinflammation predominantly mediated by microglia, thereby establishing a detrimental milieu that impedes neurological recovery. Extracellular vesicles (EVs) derived from umbilical cord mesenchymal stem cells (UCMSCs) possess considerable therapeutic potential; however, their clinical translation is constrained by insufficient bioactivity, poor targeting specificity, and uncontrolled release kinetics. Here, we present a multidimensional engineering strategy that overcomes these barriers synergistically. Tetramethylpyrazine (TMP)‐pretreated extracellular vesicles (TEVs) are enriched with anti‐inflammatory and pro‐regenerative factors in their cargo, while Angiopep‐2 (Ang2) peptide‐modified TEVs (Ang‐TEVs) confer significantly enhanced microglial targeting. A reactive oxygen species (ROS)‐responsive hyaluronic acid (HA)‐phenylboronic acid (PBA)/polyvinyl alcohol (PVA) hydrogel serves as an intelligent depot for sustained, on‐demand Ang‐TEVs release at the lesion site. This construct, Ang‐TEVs@Gel, demonstrated robust lesion accumulation and selective microglial uptake. It delivered miR‐664a‐3p, which suppressed PIK3CA to attenuate PI3K‐AKT‐mTOR signaling and unleash autophagic flux, reprogramming microglia toward a reparative state that enhanced myelin debris clearance and quelled inflammation. Consequently, axonal regeneration and remyelination were markedly improved, driving significant motor recovery in SCI mice. By integrating preconditioning, active targeting, and stimuli‐responsive biomaterials, this strategy provides an elegant blueprint for engineering EV‐based therapies to repair the injured central nervous system.
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BibTeX
@article{xiong2026multidimensional,
title = {{A Multidimensional Engineering Strategy Reprograms Microglia via Targeted and Sustained‐Release Extracellular Vesicles for Spinal Cord Injury Repair}},
author = {Wu Xiong and Minhao Liu and Mingming Zheng and Jizhou Jia and Ziyan Zhu and Guang Kong and Jie Liu and Juan Wang and Wenbo Li and Qingyuan Wang and Qian Zhu and Peiran Chan and Tao Qin and Jiayang Wu and Yongjie Zhang and Chunming Tang and Cong Li and Jin Fan},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77117},
url = {https://doi.org/10.1002/advs.77117},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Multidimensional Engineering Strategy Reprograms Microglia via Targeted and Sustained‐Release Extracellular Vesicles for Spinal Cord Injury Repair
AU - Wu Xiong
AU - Minhao Liu
AU - Mingming Zheng
AU - Jizhou Jia
AU - Ziyan Zhu
AU - Guang Kong
AU - Jie Liu
AU - Juan Wang
AU - Wenbo Li
AU - Qingyuan Wang
AU - Qian Zhu
AU - Peiran Chan
AU - Tao Qin
AU - Jiayang Wu
AU - Yongjie Zhang
AU - Chunming Tang
AU - Cong Li
AU - Jin Fan
PY - 2026
DA - 2026/08/13
JO - Advanced Science
DO - 10.1002/advs.77117
UR - https://doi.org/10.1002/advs.77117
AB - Spinal cord injury (SCI) induces neuroinflammation predominantly mediated by microglia, thereby establishing a detrimental milieu that impedes neurological recovery. Extracellular vesicles (EVs) derived from umbilical cord mesenchymal stem cells (UCMSCs) possess considerable therapeutic potential; however, their clinical translation is constrained by insufficient bioactivity, poor targeting specificity, and uncontrolled release kinetics. Here, we present a multidimensional engineering strategy that overcomes these barriers synergistically. Tetramethylpyrazine (TMP)‐pretreated extracellular vesicles (TEVs) are enriched with anti‐inflammatory and pro‐regenerative factors in their cargo, while Angiopep‐2 (Ang2) peptide‐modified TEVs (Ang‐TEVs) confer significantly enhanced microglial targeting. A reactive oxygen species (ROS)‐responsive hyaluronic acid (HA)‐phenylboronic acid (PBA)/polyvinyl alcohol (PVA) hydrogel serves as an intelligent depot for sustained, on‐demand Ang‐TEVs release at the lesion site. This construct, Ang‐TEVs@Gel, demonstrated robust lesion accumulation and selective microglial uptake. It delivered miR‐664a‐3p, which suppressed PIK3CA to attenuate PI3K‐AKT‐mTOR signaling and unleash autophagic flux, reprogramming microglia toward a reparative state that enhanced myelin debris clearance and quelled inflammation. Consequently, axonal regeneration and remyelination were markedly improved, driving significant motor recovery in SCI mice. By integrating preconditioning, active targeting, and stimuli‐responsive biomaterials, this strategy provides an elegant blueprint for engineering EV‐based therapies to repair the injured central nervous system.
SN - 2198-3844
ER -