Transdermal drug delivery platform for psoriasis: co-delivery of methotrexate and TNF-α siRNA via hydrogel microneedles.

Psoriasis is a chronic inflammatory skin disease, commonly managed using a combination of oral methotrexate (MTX) and injected TNF-α inhibitors. However, these often result in systemic side effects. Here, we report a gelatin methacryloyl-based (GelMA) hydrogel microneedle patch for the localized co-delivery of MTX and DNA tetrahedral-loaded TNF-α siRNA (MTX-TDN-siRNA MNs), integrating various administration methods into a unified transdermal platform. In an imiquimod (IMQ)-induced psoriasis mouse model, the MTX-TDN-siRNA MNs treatment demonstrated robust therapeutic efficacy, evidenced by improved PASI scores and epidermal normalization. The combined treatment strategy achieved enhanced outcomes compared to monotherapies of MTX or TNF-α siRNA. Moreover, the GelMA-based microneedles significantly reduced the MTX dosage, thereby minimizing systemic toxicity, as indicated by stable serum biochemical markers. This transdermal platform integrates chemotherapeutic and genetic agents, offering a safe, convenient, and efficient combinatory therapy for psoriasis.