Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA.
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
Nat Biomed Eng. 2021 Sep;5(9):1059-1068. doi: 10.1038/s41551-021-00786-x. Epub 2021 Oct 6.
Lipid nanoparticles (LNPs) for the efficient delivery of drugs need to be designed for the particular administration route and type of drug. Here we report the design of LNPs for the efficient delivery of therapeutic RNAs to the lung via nebulization. We optimized the composition, molar ratios and structure of LNPs made of lipids, neutral or cationic helper lipids and poly(ethylene glycol) (PEG) by evaluating the performance of LNPs belonging to six clusters occupying extremes in chemical space, and then pooling the lead clusters and expanding their diversity. We found that a low (high) molar ratio of PEG improves the performance of LNPs with neutral (cationic) helper lipids, an identified and optimal LNP for low-dose messenger RNA delivery. Nebulized delivery of an mRNA encoding a broadly neutralizing antibody targeting haemagglutinin via the optimized LNP protected mice from a lethal challenge of the H1N1 subtype of influenza A virus, and delivered mRNA more efficiently than LNPs previously optimized for systemic delivery. A cluster approach to LNP design may facilitate the optimization of LNPs for other administration routes and therapeutics.
脂质纳米颗粒 (LNPs) 可高效递药，在设计时需针对特定的给药途径和药物类型。在此，我们报告了通过雾化将治疗性 RNA 递送至肺部的 LNPs 的设计。我们通过评估属于六个占据化学空间极端的 LNPs 簇的性能，对由脂质、中性或阳离子辅助脂质和聚乙二醇（PEG）组成的 LNPs 的组成、摩尔比和结构进行了优化，并汇集了先导簇并扩大了其多样性。我们发现，PEG 的低（高）摩尔比可提高具有中性（阳离子）辅助脂质的 LNPs 的性能，这是一种鉴定出的用于低剂量信使 RNA 递药的最优 LNPs。通过优化的 LNP 经雾化递送至编码针对血凝素的广泛中和抗体的 mRNA，可保护小鼠免受甲型 H1N1 亚型流感病毒的致死性攻击，并且比之前针对全身递药优化的 LNPs 更有效地递送 mRNA。LNP 设计的聚类方法可能有助于优化用于其他给药途径和治疗方法的 LNPs。
