Psoriasis has been successfully treated by directly blocking the interleukin (IL)-23/IL-17 pathway and several inhibitors that specifically target the IL-23/IL-17 signaling axis have been approved by the Food and Drug Administration for clinical use and show excellent efficacy. However, all the approved IL-23/IL-17 axis targeting agents cannot be non-invasively delivered as topical treatment due to their biological and physicochemical properties, e.g., susceptibility to degradation, large molecular size, hydrophobicity and charge. Herein, we used novel ionic liquid biomaterials, amino acid esters and octanoic acids, as a non-invasive transdermal drug delivery system for bicyclic peptide inhibitors targeted to IL-23R and IL-17A. Using phenotypical images, psoriasis area and severity index, hematoxylin-eosin, and immunohistochemistry, we demonstrate that a biocompatible ionic liquid-based topical delivery approach of peptide inhibitors alleviates psoriasis in an imiquimod-induced psoriasis mouse model. Flow cytometry of innate lymphoid cells (ILCs) within the spleen, peripheral blood, and lesional epidermis shows that treatment with ionic liquids-peptides selectively blocks and reconfigures the spectrum of skin-resident and circulating ILCs. These results provide a framework for a topical delivery approach for peptides. Our findings highlight the potential of topical administration of peptide inhibitors of the IL-23/IL-17 pathway by biocompatible ionic liquids to treat psoriasis. The main immunopathogenic mechanism of peptide inhibitors mitigating psoriasis is reconfiguration of a spectrum of skin-resident and circulating ILCs.
