1. Ionizable lipid nanoparticles for in utero mRNA delivery
- Author
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Meghana V. Kashyap, Andrew Y. Cheng, Margaret M. Billingsley, Michael J. Mitchell, Philip W. Zoltick, Rachel S. Riley, Sourav Bose, Mohamad-Gabriel Alameh, Brandon White, William H. Peranteau, Drew Weissman, Hiaying Li, and Rui Zhang
- Subjects
02 engineering and technology ,03 medical and health sciences ,Mice ,Immune system ,Medicine ,Animals ,Luciferase ,Health and Medicine ,RNA, Messenger ,Progenitor cell ,Gene ,reproductive and urinary physiology ,Research Articles ,030304 developmental biology ,Gene Editing ,0303 health sciences ,Fetus ,Messenger RNA ,Multidisciplinary ,business.industry ,SciAdv r-articles ,Life Sciences ,021001 nanoscience & nanotechnology ,Cell biology ,Secretory protein ,In utero ,embryonic structures ,Liposomes ,Nanoparticles ,0210 nano-technology ,business ,Research Article - Abstract
Lipid nanoparticles deliver mRNA to mouse fetuses, which may ultimately enable in utero therapy to treat fetal genetic diseases., Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)–mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.
- Published
- 2019