Ionic Liquid-Mediated Sulfur Activation and Dermal Delivery for Psoriasis Treatment.

Reactive sulfur species, including supersulfides and hydrogen sulfide (H2S), have attracted attention for their anti-inflammatory and redox-modulating properties. Therefore, these sulfur species have the potential to treat inflammatory and oxidative stress-related diseases, such as psoriasis. However, their clinical application remains limited owing to instability, rapid diffusion, and difficulty in maintaining effective local concentrations at inflamed sites. In this study, we developed a thiol-functionalized ionic liquid as a redox-active delivery platform for elemental sulfur S8 to enable localized sulfur-based therapy for psoriasis. While S8 was insoluble in water, the thiol-functionalized ionic liquid solubilized S8 at 15 mg/mL. Raman spectroscopy and methylene blue assays indicated partial conversion of S8 into redox-active sulfur species. The formulation facilitated intracellular uptake of sulfur species, and it reduced 96.7% of oxidative stress in keratinocytes induced by hydrogen peroxide. Furthermore, the sulfur-containing ionic liquid also scavenged nitric oxide released from inflamed macrophages about twice as effectively as the ionic liquid without S8. Using Franz diffusion cells, sulfur species were predominantly detected within the epidermis with minimal transdermal permeation, thereby indicating effective local retention. In an imiquimod-induced psoriasiform dermatitis model, topical application of the sulfur-containing ionic liquid suppressed epidermal hyperplasia from 74.8 to 32.8 μm and reduced chemokine expression. Collectively, these findings demonstrate that a thiol-functionalized ionic liquid can function not only as a solvent but also as a reactive medium for generating and delivering redox-active sulfur species. This strategy is thought to provide a promising platform for localized redox modulation in inflammatory skin diseases, including psoriasis.