{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:03:18Z","timestamp":1791478998239,"version":"4.3.4"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio de Ciencia e Innovaci\u00f3n","award":["DIN2021-011799"],"award-info":[{"award-number":["DIN2021-011799"]}]},{"name":"Ministerio de Ciencia e Innovaci\u00f3n","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}]},{"name":"Ministerio de Ciencia e Innovaci\u00f3n","award":["IDMF\/2021\/0009"],"award-info":[{"award-number":["IDMF\/2021\/0009"]}]},{"name":"Gobierno de Arag\u00f3n","award":["DIN2021-011799"],"award-info":[{"award-number":["DIN2021-011799"]}]},{"name":"Gobierno de Arag\u00f3n","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}]},{"name":"Gobierno de Arag\u00f3n","award":["IDMF\/2021\/0009"],"award-info":[{"award-number":["IDMF\/2021\/0009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Lipid nanoparticles (LNPs) are leading mRNA delivery vehicles, with ionizable lipids (ILs) as their key component. However, the relationship between the IL structure and LNP endogenous organ-targeting is not well understood. In this study, we developed a novel library of biodegradable ILs featuring beta-propionate linkers, which, when incorporated into a four-component LNP formulation, show excellent extrahepatic selectivity and high protein expression. Methods: We explored the impact of structural modifications in the hydrophobic chains and polar-head groups in the ILs while keeping the linkers unchanged. In vivo results were evaluated to examine how structural changes influence the biodistribution to spleen or lungs. LNP formulations were assessed for their protein expression levels and organ-specific targeting. Additionally, protein corona formation by the best-performing LNPs was examined to provide further mechanistic insights. Results: Organ targeting was significantly influenced by structural changes in the ILs, allowing for precise control of the biodistribution between the spleen and lungs. Branched hydrophobic chains demonstrated a higher propensity for spleen targeting, while modifications in the polar-head group could drastically shift biodistribution from the lung to the spleen. This led to the identification of LNPs\u2019 zeta potential as a key determinant of their extrahepatic targeting properties. Notably, ionizable lipid A3T2C7, also known as CP-LC-1495, displayed strong lung selectivity (97%) and high protein expression in lung tissue (1.21 \u00d7 108 p\/s). Similarly, several promising candidates for spleen-targeting LNPs displayed protein expression levels exceeding 1 \u00d7 107 p\/s (selectivity &gt;80%). Conclusions: This study elucidates the structure\u2013function relationships of ILs in passive organ-specific mRNA delivery, highlighting how the fine-tuning of hydrophobic chains, polar-head groups, and surface charge (zeta potential) allows for the precise control of LNP endogenous biodistribution, a mechanism influenced by protein corona formation. These findings enable the rational design of targeted LNP systems, enhancing their therapeutic potential for specific organs, such as the spleen and lungs.<\/jats:p>","DOI":"10.3390\/pharmaceutics17040459","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T07:47:44Z","timestamp":1743580064000},"page":"459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Predictive Lung- and Spleen-Targeted mRNA Delivery with Biodegradable Ionizable Lipids in Four-Component LNPs"],"prefix":"10.3390","volume":"17","author":[{"given":"Juan","family":"Heredero","sequence":"first","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3517-4102","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4155-749X","authenticated-orcid":false,"given":"Esther","family":"Broset","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Bland\u00edn","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8486-8514","authenticated-orcid":false,"given":"Diego","family":"de Miguel","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9324-0446","authenticated-orcid":false,"given":"Teresa","family":"Alejo","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0087-7780","authenticated-orcid":false,"given":"Alfonso","family":"Toro","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4086-7544","authenticated-orcid":false,"given":"Elena","family":"Mata","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"L\u00f3pez-Gav\u00edn","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Gallego-Lleyda","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Casabona","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Lampaya","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Larraga","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4464-9528","authenticated-orcid":false,"given":"Esther","family":"P\u00e9rez-Herr\u00e1n","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3448-1314","authenticated-orcid":false,"given":"David","family":"Luna","sequence":"additional","affiliation":[{"name":"Certest Pharma, Certest Biotec S.L., San Mateo de G\u00e1llego, 50840 Zaragoza, Spain"},{"name":"Department of Theoretical Physics, Faculty of Science, University of Zaragoza, Pedro Cerbuna s\/n, 50009 Zaragoza, Spain"},{"name":"Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor s\/n, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7508-4750","authenticated-orcid":false,"given":"Irene","family":"Orera","sequence":"additional","affiliation":[{"name":"Proteomics Research Core Facility, Aragon Health Sciences Institute (IACS), 50009 Zaragoza, 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