ROS‐Responsive Hydrogel Delivery of miR‐665 for Alopecia Areata: Mechanistic Insights and Translational Perspectives

ABSTRACT

Alopecia areata (AA) is a common autoimmune hair‐loss disorder driven by cytotoxic T cells, interferon‐γ (IFN‐γ) signaling, and dysregulated JAK‐STAT activation. Current systemic treatments, including JAK inhibitors, are limited by safety considerations and frequent relapse after treatment discontinuation. Local nucleic acid delivery is promising but faces challenges in stability, tissue retention, and controlled release. Luo et al. recently developed a reactive oxygen species (ROS)‐responsive injectable hydrogel based on polyvinyl alcohol crosslinked with N ¹ ,N ³ ‐bis(4‐boronobenzyl)‐N ¹ ,N ¹ ,N ³ ,N ³ ‐tetramethylpropane‐1,3‐diaminium bromide (PVA‐TSPBA) for delivery of miR‐665, a microRNA targeting STAT3. This Commentary evaluates the mechanistic rationale of the miR‐665/STAT3 axis, the advantages of ROS‐responsive hydrogels for lesion‐specific release, and key translational barriers. Specific testable mechanisms are proposed for the dissociation between reduced STAT3 mRNA and stable total protein, including upstream kinases (JAK2/SRC), phosphatases (SHP‐1/PTEN), and indirect pathways. Although the system shows prolonged local retention, attenuated inflammation, and enhanced hair follicle regeneration in preclinical models, critical issues remain unresolved, including the cellular targeting spectrum of miR‐665, in vivo ROS‐dependent release kinetics, miRNA stability under oxidative conditions, and potential systemic immune effects. Single‐cell omics, spatial imaging, in vivo imaging, humanized models, and toxicological evaluation will be key to clinical translation.