Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach
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...
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2024-04-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X23003638 |
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| author | Rachel E. Young Katherine M. Nelson Samuel I. Hofbauer Tara Vijayakumar Mohamad-Gabriel Alameh Drew Weissman Charalampos Papachristou Jason P. Gleghorn Rachel S. Riley |
| author_facet | Rachel E. Young Katherine M. Nelson Samuel I. Hofbauer Tara Vijayakumar Mohamad-Gabriel Alameh Drew Weissman Charalampos Papachristou Jason P. Gleghorn Rachel S. Riley |
| author_sort | Rachel E. Young |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T05:54:12Z |
| format | Article |
| id | doaj.art-030cc556d30340f79b8eba32bbbbe63c |
| institution | Directory Open Access Journal |
| issn | 2452-199X |
| language | English |
| last_indexed | 2024-03-08T05:54:12Z |
| publishDate | 2024-04-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj.art-030cc556d30340f79b8eba32bbbbe63c2024-02-05T04:31:58ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2024-04-0134125137Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approachRachel E. Young0Katherine M. Nelson1Samuel I. Hofbauer2Tara Vijayakumar3Mohamad-Gabriel Alameh4Drew Weissman5Charalampos Papachristou6Jason P. Gleghorn7Rachel S. Riley8Department of Biomedical Engineering, Henry M. Rowan College of Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United States; School of Translational Biomedical Engineering & Sciences, Virtua College of Medicine & Life Sciences of Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United StatesDepartment of Chemical and Biomolecular Engineering, College of Engineering, University of Delaware, 150 Academy Street, Newark, DE 19716, United StatesDepartment of Biomedical Engineering, Henry M. Rowan College of Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United States; School of Translational Biomedical Engineering & Sciences, Virtua College of Medicine & Life Sciences of Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United States; Cooper Medical School of Rowan University, Rowan University, 401 Broadway, Camden, NJ 08103, United StatesDepartment of Biomedical Engineering, Henry M. Rowan College of Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United States; School of Translational Biomedical Engineering & Sciences, Virtua College of Medicine & Life Sciences of Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United StatesPerelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, United StatesPerelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, United StatesDepartment of Mathematics, College of Science & Mathematics, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United StatesDepartment of Biomedical Engineering, College of Engineering, University of Delaware, 590 Avenue 1743, Newark, DE 19713, United StatesDepartment of Biomedical Engineering, Henry M. Rowan College of Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United States; School of Translational Biomedical Engineering & Sciences, Virtua College of Medicine & Life Sciences of Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, United States; Corresponding author. 201 Mullica Hill Rd, Glassboro, NJ, 08028.United States.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.http://www.sciencedirect.com/science/article/pii/S2452199X23003638Lipid nanoparticles (LNPs)Drug deliveryNucleic acidsPlacental growth factor (PlGF)PlacentaPregnancy |
| spellingShingle | Rachel E. Young Katherine M. Nelson Samuel I. Hofbauer Tara Vijayakumar Mohamad-Gabriel Alameh Drew Weissman Charalampos Papachristou Jason P. Gleghorn Rachel S. Riley Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach Bioactive Materials Lipid nanoparticles (LNPs) Drug delivery Nucleic acids Placental growth factor (PlGF) Placenta Pregnancy |
| title | Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach |
| title_full | Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach |
| title_fullStr | Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach |
| title_full_unstemmed | Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach |
| title_short | Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach |
| title_sort | systematic development of ionizable lipid nanoparticles for placental mrna delivery using a design of experiments approach |
| topic | Lipid nanoparticles (LNPs) Drug delivery Nucleic acids Placental growth factor (PlGF) Placenta Pregnancy |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X23003638 |
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