美国宾夕法尼亚大学Michael J. Mitchell团队近期取得重要工作进展，他们研究提出，胎盘促血管内皮生长因子mRNA脂质纳米粒子可改善小鼠子痫前期症状。相关研究成果2024年12月11日在线发表于《自然》杂志上。

据介绍，子痫前期是一种胎盘疾病，影响3-5%的妊娠，是全球孕产妇和胎儿发病率的主要原因。由于没有药物可以减缓疾病进展，工程化可电离脂质纳米粒（LNP）将肝外mRNA递送到胎盘是治疗先兆子痫的一种有吸引力的治疗选择。

研究人员使用高通量筛选来评估98种LNP制剂的体内库，并鉴定出一种胎盘嗜性LNP（LNP 55），该LNP在妊娠小鼠中介导的mRNA递送量比基于美国食品和药物管理局批准的Onpattro LNP（DLin-MC3-DMA）的制剂高100倍以上。研究人员提出了一种基于β2-糖蛋白I吸附的内源性靶向机制，使LNP能够递送到胎盘。在炎症和缺氧诱导的先兆子痫模型中，单次给予包封血管内皮生长因子（VEGF）mRNA的LNP 55可解决母体高血压，直至妊娠结束。

此外，通过VEGF mRNA LNP 55治疗，研究人员证明了胎儿健康的改善，并部分恢复了胎盘血管系统、局部和全身免疫环境以及可溶性Fms样酪氨酸激酶-1的血清水平，这是先兆子痫的临床生物标志物。这些结果共同证明了这种mRNA LNP平台治疗先兆子痫等胎盘疾病的潜力。

附：英文原文

Title: Placenta-tropic VEGF mRNA lipid nanoparticles ameliorate murine pre-eclampsia

Author: Swingle, Kelsey L., Hamilton, Alex G., Safford, Hannah C., Geisler, Hannah C., Thatte, Ajay S., Palanki, Rohan, Murray, Amanda M., Han, Emily L., Mukalel, Alvin J., Han, Xuexiang, Joseph, Ryann A., Ghalsasi, Aditi A., Alameh, Mohamad-Gabriel, Weissman, Drew, Mitchell, Michael J.

Issue&Volume: 2024-12-11

Abstract: Pre-eclampsia is a placental disorder that affects 3–5% of all pregnancies and is a leading cause of maternal and fetal morbidity worldwide1,2. 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.

DOI: 10.1038/s41586-024-08291-2

Source: https://www.nature.com/articles/s41586-024-08291-2