Background: The interleukin (IL)-23/IL-17 axis plays a central role in the immunopathogenesis of psoriasis and related comorbidities by acting to stimulate keratinocyte hyperproliferation and feed-forwarding circuits of perpetual T cell-mediated inflammation. IL-23 plays a pivotal role in stimulating the production of IL-17 by activating the Th17 cells. Emerging evidence from clinical trials has shown that monoclonal antibodies (mAbs) against IL-23, IL-23R, and IL-17A/IL-17F are effective in the treatment of patients with psoriasis. Unfortunately, all the approved IL-23/IL-17 axis targeting agents cannot be non-invasively delivered as topical administration for plaque psoriasis due to their biological properties.

Objectives: We used permeation enhancers (PEs) as a non-invasive transdermal drug delivery system for bicyclic peptide inhibitors targeted to IL-23R and IL-17A.

Methods: The thermal stability and viscosity of PEs were determined by Differential Scanning Calorimeter (DSC), Thermal Gravimetric Analyzer (TGA), and Rheometer. Scanning Electron Microscopy (SEM) was used to observe the microstructure of stratum corneum (SC). Mouse skin was placed in the Franz diffusion cell for in vitro skin permeation study. Psoriasis-like mouse models established using topical imiquimod (IMQ) cream for induction. Psoriasis Area and Severity Index (PASI) be used as an objective scoring system for therapeutic efficacy. Inflammatory cytokines, keratinocyte proliferation and inflammatory cell infiltration were determined by hematoxylin-eosin (H&E) and immumohistochemical (IHC) staining. Flow cytometry was employed to analyze the presence, distribution, and subtype of innate lymphoid cells (ILCs) within the spleen, peripheral blood, and lesional epidermis.

Results: All of the PEs fused with the lipids in SC to destroy their ordered structure, and the lipid content of the SC was reduced, which led to the decrease in the absorption of the peak area of the lipids. SEM also observed the treated SC was loose and dry, with obvious gaps between the multilayers of lipids. The permeation rate of the experimental group was significantly higher in Franz diffusion study. Semi-quantitative results showed that fluorescence could be detected in the epidermis or dermis of the experimental groups, indicating that PEs could effectively deliver drugs across SC to the dermis. After administration of bicyclic peptide inhibitors with PEs, the scores of erythema, scales and wrinkles were markedly lower compared with model group. The combination of IL-23R and IL-17A inhibitors group showed the lowest PASI score, indicating its excellent anti-psoriasis efficacy. In addition, the spleen size was also significantly reduced in treatment groups. The thickness of SC, inflammatory cytokines, keratinocyte proliferation and inflammatory cell infiltration were significantly reduced in treatment groups. In model group, flow cytometry showed an enrichment of ILCs in the circulatory and lesional epidermal tissues. Although no significant reduction was observed after treatment, a notable decreasing trend was evident. Further analysis of RORgT+ positive ILC3 showed a significant decrease in treatment groups.

Conclusion: Here, we report a biocompatible PE-based bicyclic peptide delivery approach for IL-23/IL-17 axis inhibition in an psoriasis mouse model. Specifically, we have identified a combination of PEs that simultaneously stabilizes bicyclic peptides and enhances their penetration into the skin following topical application. In addition, we demonstrate the efficacy of the formulation in IL-23/IL-17 axis selective blockade and reconfiguration of a spectrum of skin-resident and circulating innate lymphoid cells.

REFERENCES: NIL.

Acknowledgements: This research was supported by grants from the National Natural Science Foundation of China (81601418), the Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2023-LCYJ-PY-03).

Disclosure of Interests: None declared.