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Cited by 145RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryAdvancements in Transdermal Drug Delivery

Ionizable Lipid Nanoparticles for In Vivo mRNA Delivery to the Placenta during Pregnancy

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Swingle, Kelsey L., Safford, Hannah C., Geisler, Hannah C., Hamilton, Alex G., Thatte, Ajay S., Billingsley, Margaret M., Joseph, Ryann A., Mrksich, Kaitlin +5 more·2023·Journal of the American Chemical Society
DOI 10.1021/jacs.2c12893PMC PMC9992266
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Abstract

Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nonviral platform for mRNA delivery. While they have been explored for applications including vaccines and gene editing, LNPs have not been investigated for placental insufficiency during pregnancy. Placental insufficiency is caused by inadequate blood flow in the placenta, which results in increased maternal blood pressure and restricted fetal growth. Therefore, improving vasodilation in the placenta can benefit both maternal and fetal health. Here, we engineered ionizable LNPs for mRNA delivery to the placenta with applications in mediating placental vasodilation. We designed a library of ionizable lipids to formulate LNPs for mRNA delivery to placental cells and identified a lead LNP that enables in vivo mRNA delivery to trophoblasts, endothelial cells, and immune cells in the placenta. Delivery of this top LNP formulation encapsulated with VEGF-A mRNA engendered placental vasodilation, demonstrating the potential of mRNA LNPs for protein replacement therapy during pregnancy to treat placental disorders.

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  • LNP 4 with ionizable lipid C12-494 was previously shown to transfect endothelial cells in the placenta after intravenous injection and induce vasodilation in the placenta after VEGF mRNA delivery.

    “LNP 4, with ionizable lipid C12–494, was previously shown to transfect endothelial cells in the placenta after intravenous injection, as well as induce vasodilation in the placenta after VEGF mRNA delivery.40”

    From Predictive High-Throughput Platform for Dual Screening of mRNA Lipid Nanoparticle Blood–Brain Barrier Transfection and Crossing (2024) · cites this paper as [40]

    The Results sections on placental-cell delivery and VEGF-mediated vasodilation report that LNP A4 delivered mRNA to placental endothelial cells in pregnant mice and increased fetal blood-vessel area after VEGF mRNA treatment. The paper describes intravenous tail-vein injection, but it identifies the formulation as LNP A4, not “LNP 4,” and does not identify its ionizable lipid as C12–494. Those formulation details are unsupported by our copy. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Swingle, K. L., Safford, H. C., Geisler, H. C., Hamilton, A. G., Thatte, A. S., Billingsley, M. M., Joseph, R. A., Mrksich, K., Padilla, M. S., 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
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2023-02-15
Volume
145
Issue
8
Pages
4691-4706
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/jacs.2c12893
PMC
PMC9992266
OpenAlex
W4320855990
Cited by
145
References
9
Citations by year
2026: 30 · 2025: 40 · 2024: 53 · 2023: 22
FWCI
12.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Center for Advancing Translational Sciences (DP2 TR002776)
  • National Cancer Institute (F31 CA260922, R01 CA241661, R37 CA244911)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK123049)
  • National Institute of Dental and Craniofacial Research (T90DE030854)
  • Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBET-2145491)
  • Burroughs Wellcome Fund
  • National Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
Keywords
ionizable lipid nanoparticles, mRNA delivery, placenta, placental insufficiency, VEGF-A, trophoblast, endothelial cells, non-viral gene delivery, protein replacement therapy, pregnancy, fetal growth restriction
MeSH terms
Female, Humans, Lipids, Liposomes, Placenta, Placental Insufficiency, Pregnancy, RNA, Messenger, RNA, Small Interfering, Endothelial Cells, Nanoparticles

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