Abstract
The high prevalence of skin diseases and their visible symptoms result in major physical, emotional, and economic burden for which few solutions exist. To address this unmet medical need, topical delivery of RNAi such as siRNA holds many advantages including direct access to the diseased site, potent knockdown of disease symptoms, and limited off-target effects. Unfortunately, delivering drugs into skin is extremely difficult. To address these concerns, we present RNAi robed with ionic liquid moieties. Specifically, we show that robed-siRNAs can be synthesized by a simple two-step process from bulk materials. Robing affords tuneability of properties necessary for dermal drug delivery including octanol-water partitioning, skin transport, and cell internalization. The efficacy and safety of robed-siRNA for treating skin disease was confirmed by its ability to limit breakdown of elastin, a major cause of premature aging, following UVB exposure to human reconstructed skin tissue. Together, the data strongly support that therapeutic RNAi robed with ionic liquid moieties are a simple, scalable prodrug platform for treating skin disease.