Non-invasive transdermal delivery of peptide inhibitors of the IL-23/IL-17 axis by novel ionic liquid biomaterials for psoriasis treatment

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, <i>e.g.</i>, 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.