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Conventional systemic therapies, including oral and injectable formulations, are often limited by adverse off-target effects, which limit their utility in long-term clinical management. To address this challenge, we developed a soluble bilayered microneedle patch (Methotrexate and dexamethasone co-loaded bilayer microneedles, MTX@DXM-MNs), which consists of an outer layer of gelatine-polyvinyl alcohol hydrogel loaded with dexamethasone (DXM) and an inner layer of aminocrystallized hyaluronic acid methacrylate hydrogel loaded with methotrexate (MTX). The patch successfully traversed imiquimod (IMQ)-induced thickened epidermis in murine models to achieve intralesional drug delivery and effectively alleviate psoriasis-like skin inflammation. Versus tacrolimus ointment (positive control), MTX@DXM-MNs markedly alleviated the manifestations of stratum corneum thickening, erythema, and scaling in a mouse model and attenuated the levels of inflammatory mediators in skin tissues and peripheral blood as well as splenic indices. In conclusion, the MTX@DXM-MN bilayered microneedle patch provides a new strategy for the efficient and safe treatment of psoriasis through the temporal and spatial synergistic effects of an outer layer for the immediate release of a hormone and an inner layer for the slow release of an immunosuppressant. Thus, this patch has potential as a future clinical alternative for the treatment of psoriasis.<\/jats:p>","DOI":"10.1038\/s41598-026-38216-0","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T08:18:37Z","timestamp":1770365917000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A bilayered microneedle patch loaded with methotrexate and dexamethasone for transdermal treatment of psoriasis"],"prefix":"10.1038","volume":"16","author":[{"given":"Ting","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Die","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianwei","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaochun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lechun","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingpei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"38216_CR1","doi-asserted-by":"publisher","first-page":"1323174","DOI":"10.3389\/fimmu.2024.1323174","volume":"15","author":"R Ma","year":"2024","unstructured":"Ma, R. et al. 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