College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Sci Adv. 2021 Mar 10;7(11). doi: 10.1126/sciadv.abe2888. Print 2021 Mar.
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 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.
我们报告了一种可溶解的微针（MN）贴片，它可以介导基于 CRISPR-Cas9 的基因组编辑剂和糖皮质激素的经皮共递送来有效治疗炎症性皮肤疾病（ISD）。MN 装载有聚合物包封的 Cas9 核糖核蛋白（RNP）靶向物和含有地塞米松（Dex）的聚合物纳米颗粒。插入皮肤后，MN 可以快速溶解，释放两种类型的纳米制剂，随后被角质形成细胞和周围免疫细胞内化，在炎症性皮下层发挥治疗作用。因此，MN 实现了 Cas9 RNP 纳米复合物和 Dex 纳米颗粒的经皮共递释，导致皮下细胞内 NLRP3 炎性小体的破坏，这被证明对减轻皮肤炎症至关重要，并为 ISD 小鼠模型中的糖皮质激素治疗提供了有效选择，包括银屑病和特应性皮炎。我们的研究为经皮递药系统的合理设计提供了创新见解，并为 ISD 的治疗定义了一种有效治疗选择。
