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A major barrier to this therapeutic goal is their instability during aerosolization for local delivery. This imparts a shear force that degrades the mRNA cargo and therefore reduces cell transfection. In addition to remaining stable upon aerosolization, mRNA LNPs must also possess the aerodynamic properties to achieve deposition in clinically relevant areas of the lungs. We addressed these challenges by formulating mRNA LNPs with SM\u2010102, the clinically approved ionizable lipid in the Spikevax COVID\u201019 vaccine. Our lead candidate, B\u20101, had the highest mRNA expression in both a physiologically relevant air\u2013liquid interface (ALI) human lung cell model and in healthy mice lungs upon aerosolization. Further, B\u20101 showed selective transfection in vivo of lung epithelial cells compared to immune cells and endothelial cells. These results show that the formulation can target therapeutically relevant cells in pulmonary diseases such as cystic fibrosis. Morphological studies of B\u20101 revealed differences in the surface structure compared to LNPs with lower transfection efficiency. Importantly, the formulation maintained critical aerodynamic properties in simulated human airways upon next generation impaction. Finally, structure\u2013function analysis of SM\u2010102 revealed that small changes in the number of carbons can improve upon mRNA delivery in ALI human lung cells. Overall, our study expands the application of SM\u2010102 and its analogs to aerosolized pulmonary delivery and identifies a potent lead candidate for future therapeutically active mRNA therapies.<\/jats:p>","DOI":"10.1002\/btm2.10580","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T03:17:01Z","timestamp":1692674221000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Optimization of ionizable lipids for aerosolizable\n                    <scp>mRNA<\/scp>\n                    lipid nanoparticles"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1335-111X","authenticated-orcid":false,"given":"Mae M.","family":"Lewis","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8233-2567","authenticated-orcid":false,"given":"Melissa R.","family":"Soto","sequence":"additional","affiliation":[{"name":"Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6242-3389","authenticated-orcid":false,"given":"Esther Y.","family":"Maier","sequence":"additional","affiliation":[{"name":"Drug Dynamics Institute The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3309-7614","authenticated-orcid":false,"given":"Steven D.","family":"Wulfe","sequence":"additional","affiliation":[{"name":"Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8568-7101","authenticated-orcid":false,"given":"Sandy","family":"Bakheet","sequence":"additional","affiliation":[{"name":"Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Obregon","sequence":"additional","affiliation":[{"name":"Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7552-363X","authenticated-orcid":false,"given":"Debadyuti","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.11.002"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201015892\u20108"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab788"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prrv.2017.03.001"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes9110538"},{"key":"e_1_2_11_7_1","unstructured":"Cystic fibrosis mutation database. 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