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Among the various mRNA delivery vehicles, lipid nanoparticles (LNPs) have emerged as promising vehicles for packaging and delivering mRNA with low immunogenicity. However, while mRNA delivery has several advantages, the delivery efficiency and stability of LNPs remain challenging for mRNA therapy. In this study, an ionizable helper cholesterol analog, 3\u03b2[L\u2010histidinamide\u2010carbamoyl] cholesterol (Hchol) lipid is developed and incorporated into LNPs instead of cholesterol to enhance the LNP potency. The p\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>a<\/jats:sub>\n                    values of the Hchol\u2010LNPs are \u22486.03 and 6.61 in MC3\u2010 and SM102\u2010based lipid formulations. Notably, the Hchol\u2010LNPs significantly improve the delivery efficiency by enhancing the endosomal escape of mRNA. Additionally, the Hchol\u2010LNPs are more effective in a red blood cell hemolysis at pH 5.5, indicating a synergistic effect of the protonated imidazole groups of Hchol and cholesterol on endosomal membrane destabilization. Furthermore, mRNA delivery is substantially enhanced in mice treated with Hchol\u2010LNPs. Importantly, LNP\u2010encapsulated SARS\u2010CoV\u20102 spike mRNA vaccinations induce potent antigen\u2010specific antibodies against SARS\u2010CoV\u20102. Overall, incorporating Hchol into LNP formulations enables efficient endosomal escape and stability, leading to an mRNA delivery vehicle with a higher delivery efficiency.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202303857","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T05:39:08Z","timestamp":1707716348000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Modulating Lipid Nanoparticles with Histidinamide\u2010Conjugated Cholesterol for Improved Intracellular Delivery of mRNA"],"prefix":"10.1002","volume":"13","author":[{"given":"Onesun","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Biochemistry College of Natural Sciences Chungnam National University  Daejeon 34134 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye\u2010youn","family":"Jung","sequence":"additional","affiliation":[{"name":"Infectious 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