Ionizable Lipid Nanoparticles for In Vivo mRNA Delivery to the Placenta during Pregnancy
Ionizable Lipid Nanoparticles for In Vivo mRNA Delivery to the Placenta during Pregnancy
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DOI：
10.1021/jacs.2c12893
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发表时间：
2023-03-01
影响因子：
15
通讯作者：
Weissman, Drew
中科院分区：
文献类型：
--
作者：
Mitchell, Michael J.;Swingle, Kelsey L.;Weissman, Drew
可电离脂质纳米颗粒（LNPs）是临床上最先进的mRNA递送非病毒平台。尽管LNPs已被探索用于疫苗和基因编辑等应用，但尚未对妊娠期间胎盘功能不全进行研究。胎盘功能不全是由于胎盘血流不足引起的，这导致母亲血压升高和胎儿生长受限。因此，改善胎盘血管舒张有利于母亲和胎儿的健康。在这里，我们设计了可电离LNPs，用于mRNA递送到胎盘，并应用于介导胎盘血管舒张。我们设计了一个可电离脂质的文库，以形成mRNA递送到胎盘细胞的LNP，并鉴定了一个先导LNP，使mRNA能够在体内递送到胎盘的滋养细胞、内皮细胞和免疫细胞。这种含有VEGF-A mRNA的顶级LNP配方的递送可产生胎盘血管舒张，表明mRNA LNP在妊娠期间用于蛋白质替代疗法治疗胎盘疾病的潜力。
Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nonviral platform for mRNA delivery. While they have been explored for applications including vaccines and gene editing, LNPs have not been investigated for placental insufficiency during pregnancy. Placental insufficiency is caused by inadequate blood flow in the placenta, which results in increased maternal blood pressure and restricted fetal growth. Therefore, improving vasodilation in the placenta can benefit both maternal and fetal health. Here, we engineered ionizable LNPs for mRNA delivery to the placenta with applications in mediating placental vasodilation. We designed a library of ionizable lipids to formulate LNPs for mRNA delivery to placental cells and identified a lead LNP that enables in vivo mRNA delivery to trophoblasts, endothelial cells, and immune cells in the placenta. Delivery of this top LNP formulation encapsulated with VEGF-A mRNA engendered placental vasodilation, demonstrating the potential of mRNA LNPs for protein replacement therapy during pregnancy to treat placental disorders.