Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark.
Eur J Pharm Biopharm. 2024 May;198:114266. doi: 10.1016/j.ejpb.2024.114266. Epub 2024 Mar 16.
Design of inhalable mRNA therapeutics is promising because local administration in the respiratory tract is minimally invasive and induces a local response. However, several challenges related to administration via inhalation and respiratory tract barriers have so far prevented the progress of inhaled mRNA therapeutics. Here, we investigated factors of importance for lipid nanoparticle (LNP)-mediated delivery of mRNA to the respiratory tract. We hypothesized that: (i) the PEG-lipid content is important for providing colloidal stability during aerosolization and for mucosal delivery, (ii) the PEG-lipid contentinfluences the expression of mRNA-encoded protein in the lungs, and (iii) the route of administration (nasal versus pulmonary) affects mRNA delivery in the lungs. In this study, we aimed to optimize the PEG-lipid content for mucosal delivery and to investigatethe effect of administration route on the kinetics of protein expression. Our results show that increasing the PEG-lipid content improves the colloidal stability during the aerosolization process, but has a negative impact on the transfection efficiencyin vitro. The kinetics of protein expressionin vivois dependent on the route of administration, and we found that pulmonaryadministration of mRNA-LNPs to mice results inmore durable protein expression than nasaladministration. These results demonstrate that the design of the delivery system and the route of administration are importantfor achieving high mRNA transfection efficiency in the respiratory tract.
可吸入 mRNA 疗法的设计具有很大的前景，因为在呼吸道内进行局部给药的侵入性较小，并且可以引起局部反应。然而，通过吸入和呼吸道屏障给药的几个相关挑战迄今为止一直阻碍了吸入型 mRNA 疗法的进展。在这里，我们研究了与脂质纳米颗粒（LNP）介导的 mRNA 递送至呼吸道相关的重要因素。我们假设：（i）PEG 脂质的含量对于在雾化过程中提供胶体稳定性和粘膜递药很重要，（ii）PEG 脂质的含量影响 mRNA 编码蛋白在肺部的表达，以及（iii）给药途径（鼻内与肺部）会影响肺部的 mRNA 递药。在这项研究中，我们旨在优化用于粘膜递药的 PEG 脂质含量，并研究给药途径对蛋白表达动力学的影响。我们的结果表明，增加 PEG 脂质的含量可以改善雾化过程中的胶体稳定性，但会对体外转染效率产生负面影响。体内蛋白表达的动力学取决于给药途径，我们发现，与鼻内给药相比，将 mRNA-LNP 肺部给药至小鼠可导致更持久的蛋白表达。这些结果表明，递送系统的设计和给药途径对于在呼吸道中实现高 mRNA 转染效率很重要。
