Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki 852-8588, Japan.
Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki 852-8501, Japan.
Int J Pharm. 2023 Apr 25;637:122896. doi: 10.1016/j.ijpharm.2023.122896. Epub 2023 Mar 25.
Intratracheal (i.t.) administration, which takes advantage of the specific structure of the respiratory system, can effectively deliver nanoparticles to the lung. Much remains unknown about the i.t. administration of messenger RNA (mRNA)-lipid nanoparticles (LNPs) and the effect of lipid composition. In this study, we administered minute amounts of mRNA-LNP solutions into mice intratracheally and investigated the effect of lipid composition on protein expression in the lungs. We first validated higher protein expression with mRNA-LNP compared to that with mRNA-PEI complex and naked mRNA. Then, we evaluated the influence of lipid composition of LNPs on the protein expression and found that: 1) decreasing the PEG molarity from 1.5% to 0.5% could significantly increase the protein expression; 2) replacing DMG-PEG with DSG-PEG could slightly increase the protein expression; 3) using DOPE instead of DSPC could increase protein expression by an order of magnitude. We successfully prepared an mRNA-LNP with optimal lipid compositions that led to robust protein expression following i.t. administration, thus providing meaningful insights into advanced development of mRNA-LNPs for therapeutic i.t. administration.
气管内（i.t.）给药利用了呼吸系统的特定结构，可以有效地将纳米颗粒递送到肺部。信使 RNA（mRNA）-脂质纳米颗粒（LNPs）的 i.t.给药及其脂质组成的影响仍有许多未知之处。在这项研究中，我们通过气管内途径向小鼠给予少量的 mRNA-LNP 溶液，并研究了脂质组成对肺部蛋白质表达的影响。我们首先验证了与 mRNA-PEI 复合物和裸露 mRNA 相比，mRNA-LNP 可实现更高的蛋白质表达。然后，我们评估了 LNPs 的脂质组成对蛋白质表达的影响，发现：1）将 PEG 摩尔浓度从 1.5%降低至 0.5%可显著增加蛋白质表达；2）用 DSG-PEG 替代 DMG-PEG 可略微增加蛋白质表达；3）用 DOPE 替代 DSPC 可使蛋白质表达增加一个数量级。我们成功制备了具有最佳脂质组成的 mRNA-LNP，通过气管内给药可实现强大的蛋白质表达，从而为治疗性 i.t. 给药的 mRNA-LNP 的高级开发提供了有意义的见解。
