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

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

Nature, 2025, vol. 637, issue 8045, 412-421

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08291-2

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