1092 Topical delivery of siRNA therapeutics into the skin using STAR particles

Small interfering RNA (siRNA) therapeutics offer promising gene silencing of disease targets in various tissues. Unlike traditional small molecules, siRNAs can be chemically optimized to target a particular tissue or cell type. This scaffold can then be reprogrammed with different target sequences for treatment of a wide array of genetically defined diseases. Unfortunately, topical delivery of macromolecules such as siRNA molecules into the skin is physically impaired by the stratum corneum barrier. A recent study from Georgia Institute of Technology (Nature Medicine 26 (2020) 341-347) described a novel delivery platform using bioengineered micro star-shaped (STAR) particles that enable increased permeability across stratum corneum. STAR particles were fabricated from biocompatible alumina and intuitively applied to skin’s surface where they effectively produced microscopic, aqueous pores. In this study we identified novel siRNA chemical architectures that support robust delivery and gene silencing in human skin ex vivo following STAR particle treatment. We found that STAR particles supported efficient delivery of several bio-conjugated siRNAs with different distribution profiles throughout the epidermis and dermis. Additionally, when these siRNA are programmed to target JAK1, a well-known signaling mediator of inflammatory pathways, we observed robust silencing in both dermis and epidermis in human skin. Our data demonstrate that STAR particles combined with siRNA offer a novel and effective treatment strategy for functional delivery of gene therapies into the skin and establish a path toward siRNA treatment of skin diseases.