Umbilical cord mesenchymal stem cell-derived exosomes delivered via a thermosensitive hydrogel ameliorate atopic dermatitis by mitigating keratinocyte mitochondrial damage through activating the Wnt/β-catenin pathway.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a high global prevalence and a multifactorial etiology. Its development is primarily attributed to defective skin barrier function, immune dysregulation, and oxidative stress-induced impairments in mitochondrial activity within keratinocytes. While mesenchymal stem cell-derived exosomes show promise as a cell-free therapy, their limited efficacy via traditional systemic administration is a major challenge. To address this, we developed a thermosensitive poloxamer hydrogel-based system for the local delivery of human umbilical cord mesenchymal stem cell-derived exosomes(hUCMSC-exo). Our in vitro studies demonstrated that hUCMSC-exo were effectively internalized by HaCaT keratinocytes, significantly mitigating inflammatory responses, abnormal differentiation, and mitochondrial damage caused by IL-4/TNF-α. Through RNA-seq and mechanistic validation, we found that hUCMSC-exo exert their protective effects by activating the Wnt/β-catenin signaling pathway, which repairs the skin barrier and reduces oxidative stress. We successfully prepared and characterized the hydrogel, confirming its excellent biocompatibility and sustained-release properties. In a MC903-induced AD mouse model, local administration of the hUCMSC-exo hydrogel significantly improved AD-like symptoms and lowered serum IgE and Th2 cytokine levels. Compared to the topical steroid mometasone furoate, our formulation demonstrated comparable efficacy with a superior safety profile. Our study is the first to combine a thermosensitive hydrogel with hUCMSC-exo for local delivery, providing a safe and effective new therapeutic strategy for AD.