{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:12:30Z","timestamp":1793722350236,"version":"4.6.1"},"reference-count":72,"publisher":"National Academy of Sciences","issue":"11","license":[{"start":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006955","name":"HHS | NIH | Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["DP2-HD098860"],"award-info":[{"award-number":["DP2-HD098860"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE1745016"],"award-info":[{"award-number":["DGE1745016"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,3,12]]},"abstract":"<jats:p>Treating pregnancy-related disorders is exceptionally challenging because the threat of maternal and\/or fetal toxicity discourages the use of existing medications and hinders new drug development. One potential solution is the use of lipid nanoparticle (LNP) RNA therapies, given their proven efficacy, tolerability, and lack of fetal accumulation. Here, we describe LNPs for efficacious mRNA delivery to maternal organs in pregnant mice via several routes of administration. In the placenta, our lead LNP transfected trophoblasts, endothelial cells, and immune cells, with efficacy being structurally dependent on the ionizable lipid polyamine headgroup. Next, we show that LNP-induced maternal inflammatory responses affect mRNA expression in the maternal compartment and hinder neonatal development. Specifically, pro-inflammatory LNP structures and routes of administration curtailed efficacy in maternal lymphoid organs in an IL-1\u03b2-dependent manner. Further, immunogenic LNPs provoked the infiltration of adaptive immune cells into the placenta and restricted pup growth after birth. Together, our results provide mechanism-based structural guidance on the design of potent LNPs for safe use during pregnancy.<\/jats:p>","DOI":"10.1073\/pnas.2307810121","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T15:12:57Z","timestamp":1709565177000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":44,"title":["Lipid nanoparticle structure and delivery route during pregnancy dictate mRNA potency, immunogenicity, and maternal and fetal outcomes"],"prefix":"10.1073","volume":"121","author":[{"given":"Namit","family":"Chaudhary","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1812-4744","authenticated-orcid":false,"given":"Alexandra N.","family":"Newby","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3248-4068","authenticated-orcid":false,"given":"Mariah L.","family":"Arral","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4837-5592","authenticated-orcid":false,"given":"Saigopalakrishna S.","family":"Yerneni","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel T.","family":"LoPresti","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose","family":"Doerfler","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7783-161X","authenticated-orcid":false,"given":"Daria M. Strelkova","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7945-353X","authenticated-orcid":false,"given":"Catalina","family":"Montoya","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2940-4241","authenticated-orcid":false,"given":"Julie S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Fox","sequence":"additional","affiliation":[{"name":"Mellon Institute Centralized Vivarium, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Coon","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7117-6158","authenticated-orcid":false,"given":"Angela","family":"Malaney","sequence":"additional","affiliation":[{"name":"Mellon Institute Centralized Vivarium, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2969-6737","authenticated-orcid":false,"given":"Yoel","family":"Sadovsky","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0100-7824","authenticated-orcid":false,"given":"Kathryn A.","family":"Whitehead","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"},{"name":"Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,3,4]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.09.013"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4297"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m3320"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e3182a9ca67"},{"key":"e_1_3_4_5_2","first-page":"1043","article-title":"Registered clinical trials comprising pregnant women in China: A cross-sectional study","volume":"13","author":"Zhao Y.","year":"2022","unstructured":"Y. Zhao , Registered clinical trials comprising pregnant women in China: A cross-sectional study. Front. Pharmacol. 13, 1043 (2022).","journal-title":"Front. Pharmacol."},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1258\/om.2009.090002"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/natrevmats.2017.56"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.09.006"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.03.010"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5277"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910603106"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-021-00358-0"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.08.007"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.03.044"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.0c00596"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00443-1"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00426-1"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2204399"},{"key":"e_1_3_4_19_2","first-page":"1","article-title":"Systematic review and meta-analysis of the effectiveness and perinatal outcomes of COVID-19 vaccination in pregnancy","volume":"131","author":"Prasad S.","year":"2022","unstructured":"S. Prasad , Systematic review and meta-analysis of the effectiveness and perinatal outcomes of COVID-19 vaccination in pregnancy. Nat. Commun. 131, 1\u20138 (2022).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","unstructured":"R. E. Young Lipid nanoparticle composition drives mRNA delivery to the placenta. bioRxiv [Preprint] (2022). https:\/\/doi.org\/10.1101\/2022.12.22.521490 (Accessed 13 October 2023).","DOI":"10.1101\/2022.12.22.521490"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c12893"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202303568"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081003"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12989-020-00342-6"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-013-1074-9"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2005.03.030"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(99)00044-3"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(90)90310-7"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201805097"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201404140"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms150916153"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(99)00006-X"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/35080570"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1177\/01926233211042270"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aat6114"},{"key":"e_1_3_4_36_2","first-page":"1","volume-title":"Messenger RNA-Based Vaccines against Infectious Diseases","author":"Alameh M.-G.","year":"2020","unstructured":"M.-G. Alameh, D. Weissman, N. Pardi, Messenger RNA-Based Vaccines against Infectious Diseases (Springer Berlin Heidelberg, 2020), pp. 1\u201335."},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.243"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2622-0"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03275-y"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/720858"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0249611"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade1444"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2021.12.008"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2015.08.007"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-016-0574-0"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60266"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00001.2005"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.01.009"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R116.731661"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.langmuir.6b02499"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2009.108"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.8b00850"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1039\/D1BM00866H"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2008.12.004"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/smsc.202200071"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102048"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-019-0378-3"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2021.102651"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00283-5"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2021.101470"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14630"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2031738"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0235-7"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.01.002"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2155"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.757400"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1011293108"},{"key":"e_1_3_4_68_2","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.117.007216","article-title":"A maternally sequestered, biopolymer-stabilized vascular endothelial growth factor (VEGF) chimera for treatment of preeclampsia","volume":"6","author":"Logue O. C.","year":"2017","unstructured":"O. C. Logue, F. Mahdi, H. Chapman, E. M. George, G. L. Bidwell, A maternally sequestered, biopolymer-stabilized vascular endothelial growth factor (VEGF) chimera for treatment of preeclampsia. J. Am. Hear. Assoc. Cardiovasc. Cerebrovasc. Dis. 6, e007216 (2017).","journal-title":"J. Am. Hear. Assoc. Cardiovasc. Cerebrovasc. Dis."},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaq0180"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.02.022"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/28.1.56"},{"key":"e_1_3_4_72_2","doi-asserted-by":"crossref","unstructured":"N. Chaudhary Lipid nanoparticle structure and delivery route during pregnancy dictates mRNA potency immunogenicity and maternal and fetal outcomes. Zenodo. https:\/\/zenodo.org\/records\/8342810. Deposited 15 September 2023.","DOI":"10.1101\/2023.02.15.528720"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2307810121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T15:14:40Z","timestamp":1709565280000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2307810121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,4]]},"references-count":72,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,3,12]]}},"alternative-id":["10.1073\/pnas.2307810121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2307810121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,4]]},"assertion":[{"value":"2023-05-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2307810121"}}