Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Small. 2024 Oct;20(41):e2303568. doi: 10.1002/smll.202303568. Epub 2023 Aug 3.
During healthy pregnancy, the placenta develops to allow for exchange of nutrients and oxygen between the mother and the fetus. However, placental dysregulation can lead to several pregnancy disorders, such as preeclampsia and fetal growth restriction. Recently, lipid nanoparticle (LNP)-mediated delivery of messenger RNA (mRNA) has been explored as a promising approach to treat these disorders. Here, iterative libraries of LNPs with varied excipient molar ratios are screened in vitro for enhanced mRNA delivery to placental cells with minimal cytotoxicity when compared to an LNP formulation with a standard excipient molar ratio. LNP C5, the top formulation identified by these screens, demonstrates a fourfold increase in mRNA delivery in vitro compared to the standard formulation. Intravenous administration of LNP C5 to pregnant mice achieves improved in vivo placental mRNA delivery compared to the standard formulation and mediates mRNA delivery to placental trophoblasts, endothelial cells, and immune cells. These results identify LNP C5 as a promising optimized LNP formulation for placental mRNA delivery and further validates the design of experiments strategy for LNP excipient optimization to enhance mRNA delivery to cell types and organs of interest.
在健康妊娠期间，胎盘会发育，以实现母体和胎儿之间营养物质和氧气的交换。然而，胎盘调节异常可导致多种妊娠疾病，如子痫前期和胎儿生长受限。最近，脂质纳米颗粒（LNP）介导的信使 RNA（mRNA）传递已被探索作为治疗这些疾病的一种很有前途的方法。在这里，通过体外筛选具有不同赋形剂摩尔比的 LNP 迭代文库，与具有标准赋形剂摩尔比的 LNP 制剂相比，在最小细胞毒性的情况下，筛选出增强 mRNA 向胎盘细胞传递的 LNP。通过这些筛选确定的顶级 LNP C5 制剂，与标准制剂相比，在体外的 mRNA 传递增加了四倍。LNP C5 静脉注射给药可提高妊娠小鼠体内胎盘 mRNA 的传递，优于标准制剂，并介导胎盘滋养层细胞、内皮细胞和免疫细胞的 mRNA 传递。这些结果表明 LNP C5 是一种很有前途的胎盘 mRNA 传递优化 LNP 制剂，并进一步验证了 LNP 赋形剂优化的实验设计策略，以增强对靶细胞和器官的 mRNA 传递。
