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

TL;DR

A new hydrogel delivers miR-665 to reduce inflammation and regrow hair in a mouse model of alopecia areata.

Contribution

A ROS-responsive hydrogel for sustained miR-665 delivery to treat alopecia areata is developed.

Findings

The PVA-TSPBA hydrogel showed ROS-dependent degradation and sustained miR-665 release.

miR-665 inhibited STAT3 phosphorylation and improved hair follicle regeneration in mice.

The treatment reduced T-cell infiltration and restored follicular structure in AA models.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s12951-026-04214-7.

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