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<p>Microglia play a dual role in tissue repair and inflammatory responses following spinal cord injury (SCI), rendering the regulation of their immune activity a key therapeutic objective during disease progression. Single‑cell RNA sequencing revealed a significant upregulation of Kv1.3 expression in microglia following SCI, implicating this channel in the initiation of early neuroinflammation. To selectively target Kv1.3, engineered extracellular vesicles displaying ShK (ShK-EVs), a highly selective Kv1.3‑blocking peptide, were developed. These ShK‑EVs efficiently accumulated at the lesion site and were preferentially internalized by activated microglia. Integrated high‑throughput miRNA sequencing and proteomic profiling indicated that ShK‑EVs possess substantial neurorepair potential. Mechanistically, ShK‑EVs suppressed M1‑type microglial polarization and reduced the secretion of pro‑inflammatory cytokines by modulating the JAK/STAT signaling pathway. This modulation resulted in reduced tissue cavitation and neuronal apoptosis, enhanced neuronal survival and axonal regeneration, and ultimately led to a significant improvement in motor function in SCI mice. Taken together, these findings identify Kv1.3 as a key regulator&#xa0;of microglial activation after SCI and provide a novel, targeted therapeutic strategy using ShK‑EVs, offering new perspectives on immunomodulation of the injury microenvironment and functional neural recovery.</p> Graphical abstract <p></p>

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Reprogramming microglia via ShK-modified extracellular vesicles promotes immunomodulation and functional recovery after spinal cord injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Zuomeng Wu,
  • Yunxiao Fang,
  • Yue Qin,
  • Yixiang Dong,
  • Cancan Wang,
  • Ruocheng Guo,
  • Qi Sha,
  • Ao Liu,
  • Chongyu Jia,
  • Tianyu Han,
  • Peiwen Song,
  • Cailiang Shen

摘要

Microglia play a dual role in tissue repair and inflammatory responses following spinal cord injury (SCI), rendering the regulation of their immune activity a key therapeutic objective during disease progression. Single‑cell RNA sequencing revealed a significant upregulation of Kv1.3 expression in microglia following SCI, implicating this channel in the initiation of early neuroinflammation. To selectively target Kv1.3, engineered extracellular vesicles displaying ShK (ShK-EVs), a highly selective Kv1.3‑blocking peptide, were developed. These ShK‑EVs efficiently accumulated at the lesion site and were preferentially internalized by activated microglia. Integrated high‑throughput miRNA sequencing and proteomic profiling indicated that ShK‑EVs possess substantial neurorepair potential. Mechanistically, ShK‑EVs suppressed M1‑type microglial polarization and reduced the secretion of pro‑inflammatory cytokines by modulating the JAK/STAT signaling pathway. This modulation resulted in reduced tissue cavitation and neuronal apoptosis, enhanced neuronal survival and axonal regeneration, and ultimately led to a significant improvement in motor function in SCI mice. Taken together, these findings identify Kv1.3 as a key regulator of microglial activation after SCI and provide a novel, targeted therapeutic strategy using ShK‑EVs, offering new perspectives on immunomodulation of the injury microenvironment and functional neural recovery.

Graphical abstract