biostudies-literatureFang LU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | National Institutes of HealthNIGMS NIH HHS1296-1305https://www.ebi.ac.uk/biostudies/studies/S-EPMC12829982biostudies-literatureUnknown15(9)The presence of a hydroxyl group at the 2'-position in its ribose makes RNA susceptible to hydrolysis. Stabilization of RNAs for storage, transport and biological application thus remains a serious challenge, particularly for larger RNAs that are not accessible by chemical synthesis. Here we present reversible 2'-OH acylation as a general strategy to preserve RNA of any length or origin. High-yield polyacylation of 2'-hydroxyls ('cloaking') by readily accessible acylimidazole reagents effectively shields RNAs from both thermal and enzymatic degradation. Subsequent treatment with water-soluble nucleophilic reagents removes acylation adducts quantitatively ('uncloaking') and recovers a remarkably broad range of RNA functions, including reverse transcription, translation and gene editing. FurNature chemistryReversible 2'-OH acylation enhances RNA stability.PMC12829982GM127295R35 GM145357R01 GM127295Jun YWXiao LKool ETFang LOnishi YfalseReversible 2'-OH acylation enhances RNA stability.The presence of a hydroxyl group at the 2'-position in its ribose makes RNA susceptible to hydrolysis. Stabilization of RNAs for storage, transport and biological application thus remains a serious challenge, particularly for larger RNAs that are not accessible by chemical synthesis. Here we present reversible 2'-OH acylation as a general strategy to preserve RNA of any length or origin. High-yield polyacylation of 2'-hydroxyls ('cloaking') by readily accessible acylimidazole reagents effectively shields RNAs from both thermal and enzymatic degradation. Subsequent treatment with water-soluble nucleophilic reagents removes acylation adducts quantitatively ('uncloaking') and recovers a remarkably broad range of RNA functions, including reverse transcription, translation and gene editing. Fur2023-01-01T00:00:00Z2023 Sep2026-06-13T05:06:34.26Z2026-06-13T03:08:42.59ZS-EPMC128299823736533410.1038/s41557-023-01246-6