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Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics
Nature Nanotechnology ( IF 38.1 ) Pub Date : 2021-06-17 , DOI: 10.1038/s41565-021-00928-x
Niels Dammes 1, 2, 3, 4 , Meir Goldsmith 1, 2, 3, 4 , Srinivas Ramishetti 1, 2, 3, 4 , Jason L J Dearling 5, 6 , Nuphar Veiga 1, 2, 3, 4 , Alan B Packard 5, 6 , Dan Peer 1, 2, 3, 4
Affiliation  

The successful in vivo implementation of gene expression modulation strategies relies on effective, non-immunogenic delivery vehicles. Lipid nanoparticles are one of the most advanced non-viral clinically approved nucleic-acid delivery systems. Yet lipid nanoparticles accumulate naturally in liver cells upon intravenous administration, and hence, there is an urgent need to enhance uptake by other cell types. Here we use a conformation-sensitive targeting strategy to achieve in vivo gene silencing in a selective subset of leukocytes and show potential therapeutic applications in a murine model of colitis. In particular, by targeting the high-affinity conformation of α4β7 integrin, which is a hallmark of inflammatory gut-homing leukocytes, we silenced interferon-γ in the gut, resulting in an improved therapeutic outcome in experimental colitis. The lipid nanoparticles did not induce adverse immune activation or liver toxicity. These results suggest that our lipid nanoparticle targeting strategy might be applied for selective delivery of payloads to other conformation-sensitive targets.



中文翻译:

用于 RNA 治疗的脂质纳米粒子的构象敏感靶向

基因表达调节策略在体内的成功实施依赖于有效的、非免疫原性的运载工具。脂质纳米颗粒是最先进的非病毒临床批准的核酸递送系统之一。然而,脂质纳米颗粒在静脉内给药后会在肝细胞中自然积累,因此,迫切需要增强其他细胞类型的摄取。在这里,我们使用构象敏感的靶向策略在白细胞的选择性子集中实现体内基因沉默,并在结肠炎小鼠模型中展示潜在的治疗应用。特别是,通过靶向 α 4 β 7的高亲和力构象整合素是炎症性肠道归巢白细胞的标志,我们沉默了肠道中的干扰素-γ,从而改善了实验性结肠炎的治疗效果。脂质纳米颗粒不会引起不利的免疫激活或肝毒性。这些结果表明,我们的脂质纳米颗粒靶向策略可用于将有效载荷选择性地递送至其他构象敏感靶标。

更新日期:2021-06-17
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