Topical Dunaliella salina-Derived Exosome Loaded with Methotrexate Alleviates Psoriasis-like Inflammation via STAT3-Dependent Th17/Treg Balance.

Background: Methotrexate (MTX) is a well-established therapeutic agent for psoriasis owing to its anti-inflammatory and immunomodulatory effects. However, its clinical use is limited by insufficient local accumulation in skin lesions and the potential risk of systemic exposure. Dunaliella salina-derived exosome (DsEXO) has favorable biocompatibility, low immunogenicity and potential skin delivery capacity, making it a promising natural nanocarrier for topical MTX delivery. This study aimed to construct Dunaliella salina-derived exosome loaded with methotrexate (DsEXO@MTX) and evaluate its therapeutic efficacy and potential mechanisms in psoriasis-like skin inflammation. Methods: DsEXO@MTX was prepared and characterized in terms of morphology, particle size, surface charge and drug-loading capacity. Cellular uptake, skin retention and tissue distribution were evaluated using fluorescence imaging and skin section analysis. Therapeutic efficacy was evaluated in an imiquimod-induced psoriasis-like mouse model by clinical scoring, histopathological examination, spleen index measurement and Ki-67 immunofluorescence staining. STAT3 phosphorylation and Th17/Treg differentiation were further examined to explore the potential immunomodulatory mechanism. Results: DsEXO@MTX exhibited a relatively uniform particle size distribution and drug-loading capacity. In vivo fluorescence imaging and skin section analysis showed that DsEXO@MTX enhanced local skin retention and promoted fluorescence distribution in epidermal and dermal regions. It significantly alleviated IMQ-induced erythema, scaling, epidermal thickening, inflammatory infiltration, splenomegaly and abnormal keratinocyte proliferation in psoriasis-like mice. Mechanistically, DsEXO@MTX reduced STAT3 phosphorylation and modulated Th17/Treg differentiation, suggesting restoration of immune balance in psoriatic inflammation. Conclusions: DsEXO@MTX represents a natural exosome-like nanovesicle-mediated topical MTX delivery system that improves local drug delivery and enhances therapeutic efficacy in IMQ-induced psoriasis-like skin inflammation, particularly when administered topically. These findings provide a potential strategy for safer and more efficient local treatment of psoriasis.