Thermosensitive Hydrogel Enables Noninvasive Extracellular Vesicle Therapy for Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by impaired barrier function and helper T cell 2 (Th2)-dominant immune dysregulation. Subcutaneous administration of mesenchymal-stem-cell-derived extracellular vesicles (MSC-EVs) has shown substantial efficacy in preclinical AD models; however, its clinical utility remains restricted by injection-associated pain and poor patient compliance, necessitating more patient-friendly delivery strategies. Here, we propose a patient-friendly, noninvasive therapeutic strategy using clinical-grade MSC-EVs incorporated into a thermosensitive hyaluronic acid/Pluronic F127 (HP) hydrogel. The optimized HP hydrogel exhibited desirable shear-thinning behavior and tunable sol-gel transition at body temperature, enabling sustained EV release. In a Dermatophagoides farinae-extract-induced AD mouse model, topical application of HP-loaded EVs (HP+EVs) suppressed AD symptoms, epidermal thickening, and mast cell infiltration, demonstrating an efficacy comparable to that of subcutaneous EV injections. Notably, HP+EV treatment down-regulated both Th2 and Th1/pro-inflammatory cytokines, restoring their levels to those in healthy controls. In addition, EVs rapidly penetrated the disrupted skin barrier in AD lesions via surface-protein-dependent mechanisms, as evidenced by the loss of permeability following proteinase K treatment. Furthermore, HP+EV treatment up-regulated barrier proteins and markedly down-regulated oxidative stress markers. This study demonstrates a major advancement in EV-based therapeutics, providing a promising noninvasive formulation for the treatment of AD.