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Formulation requires the addition of a variety of lipids (including cationic) in high amounts to form complexes with the negatively charged RNA. While this approach was successful for the development of RNA vaccines, it represents a major challenge for future developments. Increasing the lipophilicity of RNA is one possible approach to reducing the amount of lipid required. In nature, geranyl\u20102\u2010thiouridine occurs at the \u201cWobble\u201d position 34 of certain bacterial tRNAs. This work details investigations into geranylated oligonucleotides and their interactions with lipids. We developed an efficient post\u2010synthetic procedure for oligonucleotide geranylation in aqueous solutions using a geranyl\u2010sulfonium salt. We discovered that the geranyl\u2010modification can be replaced by thiol\u2010nucleophiles, enabling a reversible switch of the hydrophobic character of the oligonucleotides. We show that the geranyl\u2010modified oligonucleotides anchor onto neutral membrane structures and oil droplets. Oligonucleotides bound to the outer surface of neutral liposomes can flip to the inner membrane surface by freeze\u2010thaw cycles, leading to a protective effect against enzymatic or chemical degradation. Our work expands the scope of oligonucleotide lipidation strategies, which are of great interest in RNA delivery systems.<\/jats:p>","DOI":"10.1002\/anie.9140489","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:06:06Z","timestamp":1791108366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The tRNA\u2010Modification Geranyl\u20102\u2010Thiouridine Enables RNA\u2010Lipid Association"],"prefix":"10.1002","author":[{"given":"Johannes","family":"Singer","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Chemische Epigenetik, Department Chemie Ludwig\u2010Maximilians Universit\u00e4t M\u00fcnchen  M\u00fcnchen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Halter","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Chemische Epigenetik, Department Chemie Ludwig\u2010Maximilians Universit\u00e4t M\u00fcnchen  M\u00fcnchen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Yin","family":"Chan","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Chemische Epigenetik, Department Chemie Ludwig\u2010Maximilians Universit\u00e4t M\u00fcnchen  M\u00fcnchen Germany"},{"name":"MRC Laboratory of Molecular Biology  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7898-2831","authenticated-orcid":false,"given":"Thomas","family":"Carell","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Chemische Epigenetik, Department Chemie Ludwig\u2010Maximilians Universit\u00e4t M\u00fcnchen  M\u00fcnchen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2013.0454"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010020\u20100075\u20107"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.21.7706"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040\u20104020(98)00094\u20105"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040\u20104039(97)10322\u20107"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2018.0736"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"16958","DOI":"10.1021\/ja505986a","article-title":"Multivalent N \u2010Acetylgalactosamine\u2010Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi\u2010Mediated Gene Silencing","volume":"136","author":"Nair J. 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