Innovative Microneedle Patches for Psoriasis Treatment: A Dual Approach With Methotrexate‐Zinc and Difelikefalin for Enhanced Therapeutic Outcomes

Psoriasis is a chronic inflammatory skin disease often accompanied by pruritus and a high risk of secondary infection. To address the limitations of current therapies, we developed a dual-layer microneedle (MN) system that integrates methotrexate-zinc (MTX-Zn) for sustained anti-inflammatory and antibacterial effects with difelikefalin (DFK) for rapid antipruritic action. MTX-Zn was successfully synthesized through coordination chemistry and exhibited enhanced stability, preserved antiproliferative activity, and strong antibacterial effects. The GelMA/PVA-based microneedles showed excellent mechanical strength, efficient skin penetration, and distinct spatial drug compartmentalization. In an IMQ-induced psoriasis model, MTX-Zn/DFK MNs markedly improved clinical symptoms, reduced epidermal hyperplasia, restored immune-cell homeostasis, and decreased Th17/Th1-mediated inflammation. DFK-loaded MNs rapidly alleviated pruritus, reduced epidermal nerve-fiber density, and inhibited Schwann cell migration. Transcriptomic analysis further revealed that DFK suppressed Schwann cell EMT pathways. Together, this dual-functional microneedle platform provides a synergistic therapeutic strategy that combines rapid itch relief with long-term anti-psoriatic and antibacterial effects, representing a promising approach for improving psoriasis management.