Dual-Action Microneedle Patch Shows Promise for Psoriasis in Preclinical Study

A novel dual-layer microneedle patch that combines methotrexate-zinc (MTX-Zn) with difelikefalin demonstrated enhanced therapeutic activity in a preclinical psoriasis model, addressing several key features of the disease simultaneously, including inflammation, pruritus, immune dysregulation, and infection risk.¹ The findings suggest that microneedle-based delivery may offer a new strategy for localized psoriasis treatment while reducing some limitations associated with conventional systemic therapies.

Background on PsO Management

Psoriasis management often relies on topical therapies, phototherapy, systemic agents such as methotrexate, and biologic therapies. Although methotrexate remains a cornerstone treatment for inflammatory disease, oral administration is associated with first-pass metabolism and gastrointestinal adverse effects, while injections may reduce patient adherence because of pain and frequent dosing requirements.² The investigators sought to develop a localized delivery platform capable of improving efficacy while minimizing systemic exposure.

The researchers also focused on 2 commonly overlooked aspects of psoriasis care: chronic itch and susceptibility to skin damage and infection. To address these challenges, the study combined methotrexate with zinc, which possesses antimicrobial properties, and incorporated difelikefalin, a peripherally acting kappa opioid receptor agonist approved for the treatment of pruritus in adults undergoing hemodialysis.

Designing a Dual-Layer Microneedle System

The microneedle patch was engineered with 2 distinct layers designed to release medications at different rates. A rapidly dissolving polyvinyl alcohol (PVA) layer carried difelikefalin to provide quick antipruritic activity, while methacrylated gelatin (GelMA) microneedle tips contained the MTX-Zn complex and remained within the skin for slower, sustained drug release. Laboratory testing confirmed the successful synthesis of the MTX-Zn coordination complex and demonstrated that it retained zinc’s antibacterial activity. The complex inhibited both Escherichia coli and Staphylococcus aureus, producing substantial reductions in bacterial colony formation compared with controls.

Mechanical testing showed that the microneedles were strong enough to penetrate the skin and create microchannels extending through the stratum corneum into deeper epidermal and dermal layers without excessive tissue damage. Fluorescent imaging also verified successful compartmentalization of the two drugs within different regions of the microneedles. Drug-release studies demonstrated the intended spatiotemporal delivery profile. More than 80% of difelikefalin was released within the first hour as the PVA layer dissolved, whereas MTX-Zn was released gradually over 48 hours, supporting prolonged therapeutic exposure.

Superior Performance in a Psoriasis Mouse Model

The therapeutic potential of the platform was evaluated in an imiquimod-induced mouse model of psoriasis. Compared with other treatment approaches, the dual MTX-Zn/difelikefalin microneedle system produced the greatest overall improvement in psoriasis-like lesions. Animals treated with the dual-drug microneedles showed the most favorable Psoriasis Area and Severity Index (PASI) scores, reduced epidermal thickness, and improved skin appearance.

The treatment also reduced splenomegaly, a marker associated with systemic inflammation in this model. Importantly, no significant body weight changes were observed, and investigators found no evidence of histopathologic damage in major organs, including the heart, liver, kidneys, or lungs, suggesting a favorable safety profile in animals.

Additional analyses suggested that the microneedle system helped restore immune balance. In the psoriasis model, disease induction increased neutrophil levels and elevated the CD8+/CD4+ T-cell ratio. Treatment with MTX-Zn-containing microneedles improved these immune abnormalities, indicating immunomodulatory activity beyond local skin effects.

The study also found that difelikefalin contributed to itch control by reducing abnormal epidermal nerve-fiber density and inhibiting Schwann-cell migration and epithelial-mesenchymal transition–related pathways. Together, the agents targeted multiple disease mechanisms simultaneously.

Clinical Implications

According to the investigators, the dual-layer microneedle platform provides rapid antipruritic effects alongside sustained anti-inflammatory, immunomodulatory, and antimicrobial activity. By combining localized methotrexate delivery with itch reduction and infection-control features, the approach may represent a more comprehensive treatment strategy for psoriasis. However, the research remains preclinical, and additional studies, including long-term safety assessments, large-animal studies, and clinical trials, will be required before translation into clinical practice.

References

1. Xu X, Long C, Zhou Y, Fei L, Zhou Y, Qi M. Innovative Microneedle Patches for Psoriasis Treatment: A Dual Approach With Methotrexate-Zinc and Difelikefalin for Enhanced Therapeutic Outcomes. Small. Published online May 30, 2026. doi:10.1002/smll.73958

2. Kaur J, Zambito J, Richardson CT. Methotrexate injection site reactions: Case report and literature review. JAAD Case Rep. 2022;23:79-82. Published 2022 Mar 26. doi:10.1016/j.jdcr.2022.02.030