Scientists have long wanted a way to switch off specific chemical marks on RNA at defined sites, to clarify how those modifications shape gene regulation and disease. Yet existing editing-style systems—especially those built on catalytically inactive CRISPR (dCas) coupled to “eraser” proteins—often work inconsistently and depend on the modification type and the surrounding RNA context. This has limited both basic mechanistic studies and prospects for targeted therapeutic modulation.
In a new study, Ma and colleagues introduce RNA Modification-Blocking (RModBlock), a strategy that uses chemically modified antisense oligonucleotides (ASOs) built with locked nucleic acid (LNA) to block modification deposition directly at targeted sequence locations. Rather than recruiting eraser proteins or relying on RNA cleavage, RModBlock aims to interrupt the structural and accessibility requirements that RNA writer enzymes need to install specific chemical marks.
The authors focus on how different modifications depend on RNA structure. For m5C and pseudouridine, they show that successful installation requires a precise local structural context. By designing ASOs that sterically interfere with the formation of those contexts, RModBlock suppresses modification formation in human cells. Across representative targets, the approach inhibits the establishment of m5C and pseudouridine marks by up to 97%, demonstrating that blocking can be highly efficient when writers are structure-dependent.
Strikingly, the team extends the concept to m6A, a modification whose writer machinery does not strictly require the same kind of structural context. Even here, RModBlock ASOs reduce m6A installation substantially, suggesting that the method can generalize beyond the most structure-sensitive modifications. In comparative tests, RModBlock performance matches or surpasses dCas13-eraser-based systems when those are applicable, offering a potentially simpler and more broadly reliable alternative.
Beyond cell culture, the researchers investigate cancer-relevant targets and evaluate in vivo delivery. Using mouse liver administration, they demonstrate that the blocking strategy can operate in a physiological setting, supporting the idea that precise RNA modification control may be compatible with translational development.
Together, the work positions RModBlock as a precise, efficient, and versatile toolbox for manipulating RNA modifications without genome editing and without needing eraser proteins. By translating chemical ASO design into predictable inhibition of modification writers, the authors provide an enabling approach for mapping functional RNA marks and testing therapeutic hypotheses more systematically.
Subject of Research: Selective inhibition of RNA chemical modifications using antisense oligonucleotides.
Article Title: RModBlock antisense oligonucleotides as a universal tool for precise and efficient inhibition of RNA modifications.
Article References: Ma, M., Yao, J., Chen, W. et al. RModBlock antisense oligonucleotides as a universal tool for precise and efficient inhibition of RNA modifications. Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-026-01746-z
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41551-026-01746-z
