Document Type
Article
Version Deposited
Published Version
Open Access Funding Source
Open Access Publishing Fund
Publication Date
12-23-2023
Publication Title
Bioactive Materials
DOI
10.1016/j.bioactmat.2023.11.014
Abstract
Ionizable lipid nanoparticles (LNPs) have gained attention as mRNA delivery platforms for vaccination against COVID-19 and for protein replacement therapies. LNPs enhance mRNA stability, circulation time, cellular uptake, and preferential delivery to specific tissues compared to mRNA with no carrier platform. However, LNPs are only in the beginning stages of development for safe and effective mRNA delivery to the placenta to treat placental dysfunction. Here, we develop LNPs that enable high levels of mRNA delivery to trophoblasts in vitro and to the placenta in vivo with no toxicity. We conducted a Design of Experiments to explore how LNP composition, including the type and molar ratio of each lipid component, drives trophoblast and placental delivery. Our data revealed that utilizing C12-200 as the ionizable lipid and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as the phospholipid in the LNP design yields high transfection efficiency in vitro. Analysis of lipid molar composition as a design parameter in LNPs displayed a strong correlation between apparent pKa and poly (ethylene) glycol (PEG) content, as a reduction in PEG molar amount increases apparent pKa. Further, we present one LNP platform that exhibits the highest delivery of placental growth factor mRNA to the placenta in pregnant mice, resulting in synthesis and secretion of a potentially therapeutic protein. Lastly, our high-performing LNPs have no toxicity to both the pregnant mice and fetuses. Our results demonstrate the feasibility of LNPs as a platform for mRNA delivery to the placenta, and our top LNP formulations may provide a therapeutic platform to treat diseases that originate from placental dysfunction during pregnancy.
Recommended Citation
Young, R. E., Nelson, K. M., Hofbauer, S. I., Vijayakumar, T., Alameh, M., Weissman, D., Papachristou, C., Gleghorn, J. P., & Riley, R. S. (2024). Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach. Bioactive Materials, 34, 125-137. https://doi.org/10.1016/j.bioactmat.2023.11.014
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Comments
© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license.