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To address the limitations of current therapies, we developed a dual\u2010layer microneedle (MN) system that integrates methotrexate\u2010zinc (MTX\u2010Zn) for sustained anti\u2010inflammatory and antibacterial effects with difelikefalin (DFK) for rapid antipruritic action. MTX\u2010Zn was successfully synthesized through coordination chemistry and exhibited enhanced stability, preserved antiproliferative activity, and strong antibacterial effects. The GelMA\/PVA\u2010based microneedles showed excellent mechanical strength, efficient skin penetration, and distinct spatial drug compartmentalization. In an IMQ\u2010induced psoriasis model, MTX\u2010Zn\/DFK MNs markedly improved clinical symptoms, reduced epidermal hyperplasia, restored immune\u2010cell homeostasis, and decreased Th17\/Th1\u2010mediated inflammation. DFK\u2010loaded MNs rapidly alleviated pruritus, reduced epidermal nerve\u2010fiber density, and inhibited Schwann cell migration. Transcriptomic analysis further revealed that DFK suppressed Schwann cell EMT pathways. Together, this dual\u2010functional microneedle platform provides a synergistic therapeutic strategy that combines rapid itch relief with long\u2010term anti\u2010psoriatic and antibacterial effects, representing a promising approach for improving psoriasis management.<\/jats:p>","DOI":"10.1002\/smll.73958","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T10:52:32Z","timestamp":1780138352000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Innovative Microneedle Patches for Psoriasis Treatment: A Dual Approach With Methotrexate\u2010Zinc and Difelikefalin for Enhanced Therapeutic Outcomes"],"prefix":"10.1002","volume":"22","author":[{"given":"Xiaolong","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Burns and Plastic Surgery Shenzhen Hospital of Southern Medical University Southern Medical University  Shenzhen 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