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Background <p>Alopecia areata (AA) is an autoimmune disorder characterized by γ-interferon (IFN-γ)-driven CD8 + T-cell infiltration and overactivation of the JAK-STAT pathway; however, safe and long-acting therapies are lacking. MicroRNA (miRNA)-based interventions hold promise as alternatives, but their clinical translation is hindered by poor stability and the absence of targeted delivery systems.</p> Methods <p>We identified miR-665 as a key regulator of STAT3 in embryonic mesenchymal stem cell–derived extracellular vesicles via RNA sequencing and functional screening. An injectable, reactive oxygen species (ROS)-responsive hydrogel (PVA-TSPBA) was developed to enable localized and sustained delivery of miR-665. The physicochemical properties, miRNA release kinetics, and biocompatibility of the hydrogels were systematically characterized. Therapeutic efficacy was evaluated in an imiquimod-induced AA mouse model through macroscopic, histological, and immunohistochemical analyses.</p> Results <p>The PVA-TSPBA hydrogel exhibited excellent injectability, ROS-dependent degradation, and sustained release of miR-665. In vitro, miR-665 overexpression counteracted the IFN-γ–induced suppression of proliferation and migration in keratinocytes and dermal papilla cells by inhibiting STAT3 phosphorylation. In vivo, injection of PVA-TSPBA@miR-665 hydrogel resulted in prolonged miRNA retention, and significantly promoted hair regeneration, restored follicular structure, and reduced T-cell infiltration compared with the control groups.</p> Conclusions <p>We developed a biocompatible, ROS-responsive hydrogel platform for the local delivery of miR-665, which effectively attenuated inflammatory signaling and stimulated hair follicle regeneration in AA. This study provides a novel miRNA–biomaterial combination strategy that holds promise for targeted, durable, and safe treatment of AA.</p> Graphical abstract <p></p>

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ROS-responsive hydrogel-delivered miR-665 targets STAT3 to alleviate inflammation and promote hair follicle regeneration in alopecia areata

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月21日

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  • Wenrong Luo,
  • Wenjing Tantai,
  • Qixiang Gui,
  • Xiaohai Zhu,
  • Zheyuan Hu,
  • Xiang Jie,
  • Zhiwan Liu,
  • Yufei Li,
  • Jiansheng Zheng,
  • Lie Zhu,
  • Minjuan Wu

摘要

Background

Alopecia areata (AA) is an autoimmune disorder characterized by γ-interferon (IFN-γ)-driven CD8 + T-cell infiltration and overactivation of the JAK-STAT pathway; however, safe and long-acting therapies are lacking. MicroRNA (miRNA)-based interventions hold promise as alternatives, but their clinical translation is hindered by poor stability and the absence of targeted delivery systems.

Methods

We identified miR-665 as a key regulator of STAT3 in embryonic mesenchymal stem cell–derived extracellular vesicles via RNA sequencing and functional screening. An injectable, reactive oxygen species (ROS)-responsive hydrogel (PVA-TSPBA) was developed to enable localized and sustained delivery of miR-665. The physicochemical properties, miRNA release kinetics, and biocompatibility of the hydrogels were systematically characterized. Therapeutic efficacy was evaluated in an imiquimod-induced AA mouse model through macroscopic, histological, and immunohistochemical analyses.

Results

The PVA-TSPBA hydrogel exhibited excellent injectability, ROS-dependent degradation, and sustained release of miR-665. In vitro, miR-665 overexpression counteracted the IFN-γ–induced suppression of proliferation and migration in keratinocytes and dermal papilla cells by inhibiting STAT3 phosphorylation. In vivo, injection of PVA-TSPBA@miR-665 hydrogel resulted in prolonged miRNA retention, and significantly promoted hair regeneration, restored follicular structure, and reduced T-cell infiltration compared with the control groups.

Conclusions

We developed a biocompatible, ROS-responsive hydrogel platform for the local delivery of miR-665, which effectively attenuated inflammatory signaling and stimulated hair follicle regeneration in AA. This study provides a novel miRNA–biomaterial combination strategy that holds promise for targeted, durable, and safe treatment of AA.

Graphical abstract