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Most synthetic routes toward cationic lipids have derived from simple amine cores. Greater chemical diversity can be obtained through starting with natural products containing basic nitrogen atoms, which offers routes to more complex molecules. Natural building blocks are not extensively explored, such as aminoglycosides, which are both structurally and functionally interesting for developing new carriers for nucleic acid delivery. Herein, cationic lipid\u2010modified aminoglycosides (CLAs) are explored as a family of vehicles for messenger RNA (mRNA) delivery. CLAs are synthesized from natural existing aminoglycosides coupling with alkyl epoxides and acrylates. The top hit (GT\u2010EP10) is able to deliver Luc mRNA to C57BL\/6 mice at a dose of 0.05 mg kg<jats:sup>\u22121<\/jats:sup> to achieve a 10<jats:sup>7<\/jats:sup> average luminescence intensity in the liver. The Lox\u2010Stop\u2010Lox tdTomato mouse model is used to further demonstrate that this efficient mRNA delivery system can be potentially used for gene editing. Successful delivery of human erythropoietin mRNA shows that CLA\u2010based LNPs have promising opportunities for delivery of therapeutic nucleic acids in the future.<\/jats:p>","DOI":"10.1002\/adhm.201901487","type":"journal-article","created":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T10:12:15Z","timestamp":1582884735000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Lipid\u2010Modified Aminoglycosides for mRNA Delivery to the Liver"],"prefix":"10.1002","volume":"9","author":[{"given":"Xueliang","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Biochemistry Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuo","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3823-1931","authenticated-orcid":false,"given":"Daniel J.","family":"Siegwart","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center  Dallas TX 75390 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,28]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/natrevmats.2017.56"},{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.03.013"},{"key":"e_1_2_6_1_3","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2017.5"},{"key":"e_1_2_6_1_4","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1775"},{"key":"e_1_2_6_1_5","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2742"},{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmat3765"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3763"},{"key":"e_1_2_6_2_3","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201608450"},{"key":"e_1_2_6_2_4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606886113"},{"key":"e_1_2_6_2_5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2016.12.001"},{"key":"e_1_2_6_2_6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1520756113"},{"key":"e_1_2_6_2_7","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2019.05.004"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3471"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-017-0137-2"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.7b01356"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.2217\/nmt-2018-0033"},{"key":"e_1_2_6_5_2","first-page":"613","volume":"17","author":"Mullard A.","year":"2018","journal-title":"Nat. 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