Second-Generation Acyl Modifications Stabilize RNA, Support Translation, and Suppress Cytokine Responses.

Authors

Wenrui Zhong, Qing Sun, Linglan Fang, Sumon Pratihar, Niek N Sanders, Eric T Kool

Published in

ACS chemical biology. Oct 12, 2026. Epub Oct 12, 2026.

Abstract

Bio-reversible 2'-OH polyacylation (cloaking) has been described recently as a post-transcriptional modification strategy for stabilizing RNAs while enabling recovery of biological function after delivery into cells. Here, we probe the chemical space and utility of this method by evaluating a series of new acyl adducts for their ability to maintain protein expression levels after being substituted at high levels (ca. 25% of nucleotides) on transcripts. Reagent designs focused on the inclusion of electron-withdrawing groups near the acyl carbonyl to enhance electrophilicity. Multiple new reagents demonstrated efficient messenger RNA acylation and stabilization of the RNA against thermal cleavage for two days at 37 °C. Cellular transfection experiments with these acylated transcripts showed that certain modifications maintained native or near-native levels of translation of a protein-coding RNA, confirming the robustness of the approach across a broad set of chemotypes. We further report that protein-coding RNAs polyacylated with selected reversible acyl groups show transiently reduced proinflammatory cytokine responses relative to unmodified RNA. Together, these findings expand the functional boundaries of bio-reversible 2'-OH acylation and provide guidance for future development of RNA protection and modification strategies.

PMID:
42854114
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.

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