RNA functional control by hydrolysis reversible acylation

We present the hydrolysis reversible acylation of RNA 2′-OH for functional control. Compared with previously reported acylating reagents, our new molecule EST1A eliminated the need of toxic organic molecules in deacylation. Instead, the acylation was removed by biocompatible intracellular stimuli such as esterase and histidine. After validating the reversibility using oligonucleotides, we applied our acylating reagent on functional RNAs, including broccoli aptamer, eGFP mRNA, and eGFP siRNA, and gained activity control on them. Further inhibitory and enhancive assays in HepG2 and U87MG cells confirmed that both carboxylesterase and cholinesterase contributed to deacylation in cellulo . By taking advantage of differences in esterase expression among cell lines, our new strategy can benefit the development of cell-selective gene therapeutics.