Vasudevan Aishwarya, Jozić Antony, Curtis Allison G, Bodi Emily, Ryals Renee C, Sahay Gaurav
Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, OR 97201, USA.
Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA.
J Control Release. 2025 Mar 10;379:1022-1028. doi: 10.1016/j.jconrel.2025.01.068. Epub 2025 Feb 1.
Lipid nanoparticles (LNPs) have shown great potential in the field of gene therapy for retinal diseases. To expand on this application, we investigated LNP-mediated mRNA delivery to the anterior chamber of the eye via the intracameral (IC) route of administration. Here, we show that IC injections of LNPs facilitated protein expression and gene editing in the trabecular meshwork (TM). Administration of Cre-mRNA LNPs to Ai9 mice resulted in robust tdTomato expression in the angle and corneal endothelium. In C57BL/6 mice, mCherry-mRNA LNPs demonstrated localized protein expression in the TM, which peaked at 72 h and subsequently declined over 120 h. Additionally, LNPs encapsulating Cas9 mRNA with sgAi9 enabled in vivo gene editing in Ai9 mice, with up to 14.3 % editing efficiency. This induced tdTomato expression in the iridocorneal angle, validating the potential of LNPs for gene editing applications. Importantly, no ocular toxicity was observed, indicating the safety of the IC LNP administration. Our findings highlight the use of LNPs for targeted gene therapy and editing, paving the path for the treatment of diseases such as glaucoma in the anterior eye.
脂质纳米颗粒（LNPs）在视网膜疾病的基因治疗领域已显示出巨大潜力。为了拓展这一应用，我们研究了通过前房内（IC）给药途径将LNP介导的mRNA递送至眼前房。在此，我们表明经IC注射LNP可促进小梁网（TM）中的蛋白质表达和基因编辑。向Ai9小鼠注射Cre-mRNA LNP导致在房角和角膜内皮中出现强烈的tdTomato表达。在C57BL/6小鼠中，mCherry-mRNA LNP在TM中表现出局部蛋白质表达，在72小时达到峰值，随后在120小时内下降。此外，用sgAi9封装Cas9 mRNA的LNP能够在Ai9小鼠中进行体内基因编辑，编辑效率高达14.3%。这在虹膜角膜角诱导了tdTomato表达，验证了LNP在基因编辑应用中的潜力。重要的是，未观察到眼部毒性，表明IC注射LNP的安全性。我们的研究结果突出了LNP在靶向基因治疗和编辑中的应用，为眼前部青光眼等疾病的治疗铺平了道路。
