Pre-eclampsia is a placental disorder that affects 3–5% of all pregnancies and is a leading cause of maternal and fetal morbidity worldwide^1,2. With no drug available to slow disease progression, engineering ionizable lipid nanoparticles (LNPs) for extrahepatic messenger RNA (mRNA) delivery to the placenta is an attractive therapeutic option for pre-eclampsia. Here we use high-throughput screening to evaluate a library of 98 LNP formulations in vivo and identify a placenta-tropic LNP (LNP 55) that mediates more than 100-fold greater mRNA delivery to the placenta in pregnant mice than a formulation based on the Food and Drug Administration-approved Onpattro LNP (DLin-MC3-DMA)³. We propose an endogenous targeting mechanism based on β₂-glycoprotein I adsorption that enables LNP delivery to the placenta. In both inflammation- and hypoxia-induced models of pre-eclampsia, a single administration of LNP 55 encapsulating vascular endothelial growth factor (VEGF) mRNA resolves maternal hypertension until the end of gestation. In addition, with our VEGF mRNA LNP 55 therapeutic, we demonstrate improvements in fetal health and partially restore placental vasculature, the local and systemic immune landscape and serum levels of soluble Fms-like tyrosine kinase-1, a clinical biomarker of pre-eclampsia¹. Together, these results demonstrate the potential of this mRNA LNP platform for treating placental disorders such as pre-eclampsia.

先兆子痫是一种胎盘疾病，影响所有妊娠的 3-5%，是全世界孕产妇和胎儿发病率的主要原因^1,2。由于没有药物可以减缓疾病进展，将肝外信使 RNA （mRNA） 递送到胎盘的工程化脂质纳米颗粒 （LNP） 是子痫前期的一种有吸引力的治疗选择。在这里，我们使用高通量筛选来评估体内 98 种 LNP 制剂的文库，并确定一种胎盘嗜性 LNP （LNP 55），它与基于美国食品和药物管理局批准的 Onpattro LNP （DLin-MC3-DMA^{） 的}制剂相比，介导妊娠小鼠向胎盘的 mRNA 递送量高 100 倍以上3。我们提出了一种基于₂-糖蛋白 I 吸附β内源性靶向机制，使 LNP 能够递送到胎盘。在炎症和缺氧诱导的子痫前期模型中，单次施用包裹血管内皮生长因子 （VEGF） mRNA 的 LNP 55 可解决产妇高血压，直至妊娠结束。此外，通过我们的 VEGF mRNA LNP 55 疗法，我们证明了胎儿健康的改善，并部分恢复了胎盘脉管系统、局部和全身免疫景观以及可溶性 Fms 样酪氨酸激酶-1 的血清水平，这是先兆子痫¹ 的临床生物标志物。总之，这些结果证明了这种 mRNA LNP 平台治疗胎盘疾病（如先兆子痫）的潜力。