Placenta-tropic VEGF mRNA lipid nanoparticles ameliorate murine pre-eclampsia
Open accessAbstract
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 β 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.
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- Authors
- Swingle, K. L., Hamilton, A. G., Safford, H. C., Geisler, H. C., Thatte, A. S., Palanki, R., Murray, A. M., Han, E. L., Mukalel, A. J., Han, X., Joseph, R. A., Ghalsasi, A. A., Alameh, M.-G., Weissman, D., & Mitchell, M. J.
- Affiliations
- University of Pennsylvania (US)
- Abramson Cancer Center (US)
- Corresponding author
- Mitchell, Michael J.
- ORCID
- Venue
- Nature
- Published
- 2024-12-11
- Volume
- 637
- Issue
- 8045
- Pages
- 412-421
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC12205896
- OpenAlex
- W4405268646
- Cited by
- 129
- References
- 10
- Citations by year
- 2026: 72 · 2025: 56 · 2024: 1
- FWCI
- 17.56
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-02-03)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation (CAREER, 2145491)
- University of Pennsylvania
- National Institutes of Health (DP2TR002776, NICHD‐R01, CA010815)
- National Heart, Lung, and Blood Institute (CA010815)
- National Cancer Institute (CA010815, P30 016520, P30CA010815)
- Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBET-2145491, 2145491)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD115877)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- preeclampsia, VEGF mRNA, maternal hypertension, fetal well-being, placental vasculature, soluble fms-like tyrosine kinase-1, placental inflammation, placental hypoxia
- MeSH terms
- Animals, Disease Models, Animal, Female, Lipids, Liposomes, Male, Placenta, Pre-Eclampsia, Pregnancy, RNA, Messenger, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor A, Mice, Nanoparticles
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