Researchers have developed a novel dual-drug microneedle system that combines rapid itch relief with long-lasting anti-inflammatory and antimicrobial activity.
A novel dual-layer microneedle patch that delivers both sustained anti-inflammatory therapy and rapid itch relief for psoriasis has demonstrated significant improvements in disease severity, immune dysregulation, and pruritus in a preclinical study.
The researchers say the strategy may pave the way for more comprehensive topical management of the chronic skin condition.
Published in Small, the study describes a novel transdermal drug-delivery platform that combines a methotrexate-zinc (MTX-Zn) coordination complex with difelikefalin, a selective peripherally acting kappa-opioid receptor agonist.
“Transdermal drug delivery offers an attractive alternative route for treating dermatological diseases,” the researchers wrote.
“This method enables direct targeting of the lesion site on the skin, thus minimizing the adverse side effects associated with systemic drug exposure and enhancing patient compliance.
“Microneedle (MN) technology represents a promising approach for transdermal drug delivery, offering benefits such as painlessness, reduced invasiveness, and improved efficiency.”
The researchers designed the system to address several major challenges in psoriasis management simultaneously, including chronic inflammation, persistent itch, epidermal hyperproliferation, and increased susceptibility to skin infections.
“Globally, approximately 125 million people are affected by psoriasis, which imposes a substantial physical and psychological burden on patients, often leading to depression, anxiety, and even suicidal tendencies,” they wrote.
“Despite continuous advances in therapeutic approaches, significant challenges remain, including suboptimal efficacy in certain patients and the occurrence of adverse effects. Therefore, there is an urgent need to develop more effective and safer treatment strategies for psoriasis.”
Although methotrexate remains a cornerstone treatment for moderate-to-severe disease, oral administration can be limited by gastrointestinal adverse effects and first-pass hepatic metabolism, while injectable formulations may be associated with discomfort and poor adherence.
In addition, conventional therapies do not always adequately control psoriasis-associated pruritus, a symptom that contributes significantly to impaired quality of life and may worsen disease through scratching.
To overcome these limitations, the research team engineered a dual-drug microneedle platform using methacrylated gelatin (GelMA) and polyvinyl alcohol (PVA). The lower portion of the microneedle contained difelikefalin embedded within rapidly dissolving PVA, while the upper tip contained the methotrexate-zinc complex incorporated into GelMA.
This configuration enabled spatially separated drug loading and controlled release, allowing difelikefalin to be delivered immediately after skin penetration and methotrexate-zinc to be released gradually over an extended period.
The methotrexate-zinc complex was synthesised through a coordination reaction between methotrexate and zinc chloride.
Structural analyses using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and elemental analysis confirmed successful complex formation.
The resulting compound demonstrated enhanced thermal and chemical stability compared with methotrexate alone, remaining stable over seven days without detectable degradation. The addition of zinc also conferred antibacterial properties while preserving methotrexate’s pharmacological activity.
In cellular studies, MTX-Zn inhibited the proliferation of keratinocytes and fibroblasts, two cell types implicated in the pathogenesis of psoriasis.
The antiproliferative effects were comparable to those observed with methotrexate alone, with both treatments inducing cell-cycle arrest and reducing cellular growth. Importantly, the investigators found that the introduction of zinc did not diminish methotrexate’s therapeutic effects.
The complex also demonstrated potent antibacterial activity, the researchers noted.
Testing against both Escherichia coli and Staphylococcus aureus revealed substantial reductions in bacterial growth and significant disruption of bacterial morphology.
Electron microscopy showed membrane damage, cellular collapse, and structural irregularities in treated organisms, supporting the retention of zinc-mediated antimicrobial activity within the coordination complex.
The researchers said this property may be particularly relevant in psoriasis, where barrier disruption and scratching increase the risk of secondary infection.
Mechanical testing confirmed that the microneedles possessed sufficient strength to penetrate the stratum corneum, with a failure force of 0.098 N per needle, exceeding the minimum force generally required for effective skin penetration.
Histological examination following application demonstrated successful formation of microchannels extending into the epidermis and dermis without excessive tissue damage. Fluorescent imaging confirmed distinct localisation of the two therapeutic agents within separate regions of the microneedle tips.
Drug-release studies demonstrated a clear biphasic delivery profile. More than 80% of difelikefalin was released within the first hour as the PVA component dissolved rapidly after insertion into the skin.
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In contrast, the GelMA-based tip remained embedded and gradually released MTX-Zn over approximately 48 hours, supporting prolonged local drug exposure and sustained therapeutic activity.
The therapeutic efficacy of the system was evaluated in an imiquimod-induced mouse model of psoriasis.
Animals treated with the dual-layer MTX-Zn/difelikefalin microneedles exhibited the greatest reduction in psoriasis-like symptoms compared with all comparator groups, including methotrexate-only, difelikefalin-only and blank microneedle controls.
Clinical assessments demonstrated substantial reductions in erythema, scaling and skin thickening, accompanied by lower Psoriasis Area and Severity Index (PASI) scores. Histological analysis confirmed marked improvements in epidermal hyperplasia and inflammatory skin pathology.
The treatment also reduced splenomegaly, a recognised marker of systemic immune activation in the imiquimod model, the researchers said.
Flow cytometric analysis revealed restoration of immune-cell balance within the spleen, including reductions in neutrophil infiltration and normalisation of CD8+/CD4+ T-cell ratios.
Treatment also increased the proportion of regulatory T cells while significantly decreasing Th17 and Th1 populations, both of which are known to drive psoriatic inflammation through production of cytokines such as IL-17A, interferon-gamma and tumour necrosis factor.
These findings suggested the microneedle-delivered MTX-Zn complex exerted meaningful immunomodulatory effects beyond local suppression of keratinocyte proliferation, the researchers said.
“In an IMQ-induced psoriasis model, this dual-drug microneedle system significantly improved disease severity, reduced epidermal hyperplasia and splenomegaly, and restored immune-cell homeostasis,” they concluded.
“Overall, this minimally invasive platform offers a comprehensive therapeutic strategy that simultaneously targets pruritus, epidermal hyperproliferation, immune dysregulation, and infection risk in psoriasis.
“Notably, this study is currently limited to preclinical evaluation in animal models. Further investigations, including long-term safety assessment, validation in large-animal models, and clinical studies, will be required to support future clinical translation.”
