Nature communicationsJan 10, 2026

A programmable RNA-cutting molecule that controls RNA signals

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 11, 2026

Abstract

A programmable, RNA trigger-activated ribozyme platform enables direct functional transduction of RNA signals.

The UNlocked by Activating RNA (UNBAR) platform consists of a single RNA strand that can activate diverse non-coding RNA effectors.
Ribozymes can be engineered to remain nearly inactive without a specific RNA trigger, demonstrating single-nucleotide specificity.
The platform allows for cell-free sensing and amplification of microRNA and viral RNA sequences.
A cleaved aptamer within the system releases fluorescence that correlates directly with the presence of trigger RNA.
Functionality in living cells is demonstrated by trigger-dependent regulation of CRISPR-Cas9 editing in zebrafish embryos and human cells.

Simplified

RNA detection applications can be augmented if a sensed RNA can be directly functionally transduced. However, there is no generalisable approach that allows an RNA trigger itself to directly activate diverse non-coding RNA effectors. Here, we report engineering of a programmable, RNA trigger-activated, dual-site self-cleaving ribozyme with modular sensing domain and cleavage product. This platform, UNlocked by Activating RNA (UNBAR), is entirely encoded within one RNA strand. The ribozyme can be designed to be almost completely inactive in absence of trigger, and to exhibit single-nucleotide trigger specificity. UNBAR ribozymes carry out cell-free sensing and protein-free amplification of microRNA and viral RNA sequences, and trigger-dependent release of ncRNA effectors sgRNA, shRNA and aptamer. We demonstrate RNA detection and functional transduction by a cleaved aptamer, whose fluorescence can be directly read out as a function of trigger RNA. We further engineer the ribozyme for function in cells, and demonstrate trigger-dependent regulation of CRISPR-Cas9 editing by sgRNA-embedded ribozymes in zebrafish embryos and human cells. UNBAR is a first-in-class modality with potential to be developed into a versatile platform for synthetic biology, diagnostics and gene regulation.

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Funding

Competing interests

Competing interests: S.S.A., M.L., C.T., C.S.S., S.J.T., S.K.P. and C.H.K. are inventors on patent applications related to the ribozymes described in this paper. The remaining authors declare no competing interests.

PubMed

A programmable RNA-cutting molecule that controls RNA signals

Abstract

Full Text

Funding

Competing interests

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