Microneedle-assisted genome editing: A transdermal strategy of targeting NLRP3 by CRISPR-Cas9 for synergistic therapy of inflammatory skin disorders

We report a dissolvable microneedle (MN) patch that can mediate transdermal codelivery of CRISPR-Cas9–based genome-editing agents and glucocorticoids for the effective treatment of inflammatory skin disorders (ISDs). The MN is loaded with polymer-encapsulated Cas9 ribonucleoprotein (RNP) targeting NLRP3 and dexamethasone (Dex)–containing polymeric nanoparticles. Upon insertion into the skin, the MN can be dissolved quickly to release two types of nanoformulations, which are subsequently internalized by keratinocytes and surrounding immune cells to exert their therapeutic effects in the inflammatory subcutaneous layers. Thus, the MN-enabled transdermal codelivery of Cas9 RNP nanocomplexes and Dex nanoparticles result in the disruption of subcutaneous intracellular NLRP3 inflammasomes, which is demonstrated to be critical to alleviate skin inflammations and contributes to glucocorticoid therapy in mouse models of ISDs, including psoriasis and atopic dermatitis. Our study offers innovative insights into the rational design of transdermal delivery systems and defines an effective therapeutic option for the treatment of ISDs.