Toward Long-Acting Psoriasis Therapy with Phloretin-Loaded Microneedle Patches: Insights from <i>In Vitro</i> Patient-Derived Skin Models

Plaque psoriasis is a chronic inflammatory skin disorder characterized by excessive T lymphocyte infiltration and keratinocyte hyperproliferation, resulting in epidermal thickening. Current treatments often require lifelong administration and carry risks of systemic toxicity, limiting patient adherence. Microneedle patches represent a promising alternative, offering localized, minimally invasive, and controlled drug delivery. This study evaluates the therapeutic potential of a sustained-release microneedle patch delivering phloretin or methotrexate using a tissue-engineered human psoriatic skin model. The model was developed using keratinocytes and fibroblasts isolated from lesional skin of patients with psoriasis, preserving the disease's genetic profile. Human T lymphocytes were incorporated to replicate the inflammatory microenvironment. This study demonstrates a significant reduction in epidermal thickness while no changes were observed in healthy skin substitutes, confirming specificity for hyperproliferative tissue. The therapeutic effect was comparable to systemic methotrexate. To assess molecular diffusion, Cy5-COOH was used as a fluorescent tracer, revealing sustained dermal and longitudinal diffusion for up to 2 weeks. These results suggest that a single application could provide extended therapeutic benefit for at least 2 weeks. This is the first study to demonstrate the efficacy of microneedle patch treatment in a human psoriatic skin model, supporting their potential as a targeted, long-acting therapy for psoriasis.