Aptamer-mediated multivalent endogenous ADAR1 recruitment for highly efficient RNA editing

Adenosine-to-inosine RNA editing mediated by endogenous ADAR enzymes represents a promising therapeutic strategy because it can correct mutations at the transcript level without inducing permanent changes to the genome. However, existing systems face challenges, particularly the limited editing efficiency, which limits their practical applications. Here we introduce MARRS (multivalent ADAR1-recruiting RNA editing system)-an efficient and specific RNA editing platform that leverages engineered multivalent RNA aptamers to robustly recruit endogenous ADAR1 enzymes. By optimizing aptamers targeting the Zα domain of ADAR1 p150 and embedding them in a circular RNA scaffold, MARRS enables near-complete adenosine-to-inosine editing of RNA targets in cultured cells and mouse models, achieving efficiencies up to 100% in vitro and 84% in vivo. MARRS also exhibits remarkable versatility across a range of transcript targets while maintaining high specificity with minimal off-target effects. Operating without the need for exogenous enzymes, the MARRS system offers a safe, efficient and programmable platform.