RT Journal Article
SR Electronic
T1 Lipid Nanoparticle Composition Drives mRNA Delivery to the Placenta
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.12.22.521490
DO 10.1101/2022.12.22.521490
A1 Rachel E. Young
A1 Katherine M. Nelson
A1 Samuel I. Hofbauer
A1 Tara Vijayakumar
A1 Mohamad-Gabriel Alameh
A1 Drew Weissman
A1 Charalampos Papachristou
A1 Jason P. Gleghorn
A1 Rachel S. Riley
YR 2022
UL http://biorxiv.org/content/early/2022/12/22/2022.12.22.521490.abstract
AB 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 have yet to be developed for safe and effective mRNA delivery to the placenta as a method 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 a specific combination of ionizable lipid and phospholipid in the LNP design yields high transfection efficiency in vitro. Further, we present one LNP platform that exhibits highest delivery of placental growth factor mRNA to the placenta in pregnant mice, which demonstrates induced protein synthesis and secretion of a 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. Our top LNPs may provide a therapeutic platform to treat diseases that originate from placental dysfunction during pregnancy.Competing Interest StatementThe authors have declared no competing interest.LNPlipid nanoparticlePEGpolyethylene glycolDOEdesign of experimentsHELLPhemolysis, elevated liver enzymes, low platelet countsFlt-1soluble fms-like tyrosine kinase-1PlGFplacental growth factorVEGFR1vascular endothelial growth factor receptor-1DSDdefinitive screening designDOPE1,2-dioleoyl-sn-glycero-3-phosphoethanolamineDSPC1,2 distearoyl-sn-glycero-3-phosphocholineDMPE-PEG1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt)TNS[6-(p-toluidinyl)naphthalene-2-sulfonic acid]ALTalanine aminotransferaseASTaspartate aminotransferaseIL-6interleukin-6