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

• 成果类型: Article
• 署名作者: 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.
• 署名单位: University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3156
• DOI: 10.1038/s41586-024-08291-2
• 发表日期: 2025-01-09
• 页码: 412-+
• 关键词: uterine blood-flow; in-vivo; transtrophoblastic channels; hematopoietic stem; nonviral vectors; gene-therapy; delivery; overexpression; therapeutics; adenovirus

摘要

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 beta(2)-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-eclampsia(1). Together, these results demonstrate the potential of this mRNA LNP platform for treating placental disorders such as pre-eclampsia.