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Lipid nanoparticles (LNP) are the most clinically advanced delivery vehicles for mRNA drugs and crucially rely on ionizable cationic lipids. However, the structure\u2010function relationships between ionizable lipids and efficient in\u2010vivo mRNA delivery remain poorly understood. Here, we focus on the rational design and sequential structural optimization of our ionizable lipids that performed well in vitro, but not in vivo. Through two distinct iterative optimization cycles\u2014targeting the lipid tail and the headgroup\u2014we studied how fusogenicity and pKa of ionizable lipids contribute to LNP delivery performance, in vivo. By engineering lipids with both unsaturated tails and more hydrophobic amino headgroups, we achieved both significant improvement of protein expression in vitro, reduced hemolysis risk, and more than 200\u2010fold improvement of in vivo mRNA delivery. When compared head\u2010to\u2010head to a market\u2010approved LNP benchmark, the newly developed ionizable lipids\/LNP resulted in equally highly efficient in vivo mRNA delivery, with strong liver and spleen tropism upon intravenous injection, while matching the safety of the approved platform. Our findings are pivotal for the development of next\u2010generation mRNA\u2010LNP therapies and vaccines.<\/jats:p>","DOI":"10.1002\/adhm.202501037","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T03:05:13Z","timestamp":1746414313000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Rational Design of Unsaturated, Thioether Ionizable Lipids for Enhanced In Vivo mRNA Delivery"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9804-4869","authenticated-orcid":false,"given":"Eleni","family":"Samaridou","sequence":"first","affiliation":[{"name":"Merck KGaA  Frankfurter Str. 250 64293 Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3974-4691","authenticated-orcid":false,"given":"Johanna","family":"Simon","sequence":"additional","affiliation":[{"name":"Merck KGaA  Frankfurter Str. 250 64293 Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Beck\u2010Broichsitter","sequence":"additional","affiliation":[{"name":"Merck KGaA  Frankfurter Str. 250 64293 Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2264-5518","authenticated-orcid":false,"given":"Gary","family":"Davidson","sequence":"additional","affiliation":[{"name":"ScreenFect GmbH  Lauterstr. 5a 76344 Eggenstein\u2010Leopoldshafen Germany"},{"name":"Institute of Biological and Chemical Systems (IBCS\u2010FMS) Karlsruhe Institute of Technology (KIT)  Kaiserstrasse 12 76131 Karlsruhe Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5975-948X","authenticated-orcid":false,"given":"Pavel A.","family":"Levkin","sequence":"additional","affiliation":[{"name":"ScreenFect GmbH  Lauterstr. 5a 76344 Eggenstein\u2010Leopoldshafen Germany"},{"name":"Institute of Biological and Chemical Systems (IBCS\u2010FMS) Karlsruhe Institute of Technology (KIT)  Kaiserstrasse 12 76131 Karlsruhe Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-023-00002-2"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11030658"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14122682"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202204692"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-023-00977-5"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.06.002"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2024.114235"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(00)00343-6"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2005.06.014"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0429"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41563-024-01867-3"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27493-0"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/anbr.202300006"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3TB00649B"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-022-03460-2"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-021-00358-0"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnanoscienceau.2c00062"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dmpk.2021.100424"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2022.114416"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45422-9"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2023.04.005"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2023.100572"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1811276115"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.4c07615"},{"key":"e_1_2_8_25_1","unstructured":"M. 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