Nanoparticle-coupled topical methotrexate can normalize immune responses and induce tissue remodeling in psoriasis.

Methotrexate (MTX) is an anti-proliferative drug used for treating inflammatory diseases including psoriasis. Nevertheless, its use in localized therapy is impeded due to poor transdermal penetration. We show that MTX coupled with gold-nanoparticles (GNPs) demonstrates superior anti-inflammatory efficacy compared to MTX-alone in an imiquimod (IMQ)-induced mouse model, significantly reducing γδ T cells, CD4 T cells, and neutrophils. Furthermore, it was well tolerated upon systemic and topical administration. In an AGR129 human xenograft mouse model, two-week topical treatment with MTX-GNPs inhibited skin hyperplasia significantly better than topical calcipotriol-betamethasone (TCB) and led to profound tissue remodeling, involving upregulation of extracellular matrix reorganization and downregulation of cornification and keratinization processes. The number of resident T cells in the grafts as well as IL-17 production drastically decreased upon MTX-GNP treatment. While both MTX and MTX-GNPs directly prevented proliferation and induced apoptosis of T cells, suppression of cytokine production was a shared mechanism of GNP and MTX-GNPs. In conclusion, MTX-GNPs influence immune and stromal components of the skin, leading to potent inhibition of pathogenesis in preclinical psoriasis. MTX-GNPs surpass the efficacy of conventional MTX and standard of care, emerging as a non-steroidal, topical alternative for psoriasis treatment.