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

ABSTRACT 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.