Targeting the IL-17 receptor using liposomal spherical nucleic acids as topical therapy for psoriasis.

Activation of Th17 signaling plays a critical role in psoriasis pathogenesis, and systemically-administered IL-17 inhibitors are highly effective therapy for moderate-to-severe disease. We generated topically-delivered gene-regulating nanoconstructs, comprised of spherically-arrayed antisense DNA (liposomal spherical nucleic acids/L-SNAs), which are able to penetrate human skin to knock down cutaneous gene targets. Topically-applied L-SNAs targeting the gene encoding the mouse IL-17A receptor (Il17ra) reversed the development of psoriasis clinically, histologically, and transcriptionally in imiquimod-treated psoriasis-like mouse skin. Il17ra L-SNAs reduced the modified Psoriasis Area and Severity Index (mPASI) by 74% vs. controls and decreased epidermal thickness by 56%. Il17ra L-SNA reduced Il17ra protein expression by 75% and significantly decreased mRNA expression of psoriasis markers, including Defb4, Il17c, S100a7, Pi3, Krt16, and Tnfa vs. scrambled SNA controls. A human IL17RA L-SNA penetrates 3D cultures and normal human explants to knock down IL17RA mRNA by 63% and 66%, respectively. After topical application to psoriatic 3D rafts, anti-human IL17RA L-SNAs reduced expression of IL17RA (by 72%) and IL-17-induced genes IL17C (by 85%), DEFB4 (83%), TNFA (77%), and PI3 (65%) vs. scrambled L-SNA and vehicle controls (all p<0.001). Taken together, these data suggest that targeted suppression of IL17RA is a promising new topical treatment strategy for psoriasis.