Evolution of Engineered ADAR-Based RNA Editing Systems

RNA editing is a way to diversify, regulate expression, and expand the cell transcriptome. The most common RNA editing is the reversible conversion of adenosine (A) to inosine (I) driven by double-stranded RNA-binding adenosine deaminases (ADARs). As inosine is recognized as guanosine (G) during translation, the RNA editing may result in non-synonymous codon changes. For this reason, ADARs have gained attention as promising enzymes to rewrite mRNA. Many efforts were undertaken to engineer a precise, effective, and controllable ADAR-based system to target certain Adenines on RNA to repair pathological mutations. This review summarizes the advances in ADAR-mediated RNA editing, evolving from systems using antisense oligonucleotides as guide RNA to recruit endogenous or overexpressed ADARs, through more complex setups additionally expressing other RNA-binding proteins, to rational designs harnessing ADARs to convert other nucleotides and amplify the low initial signal. Increasing the specificity and yield of RNA editing, expanding the number of targetable sites, and reducing off-target and bystander activity remain key challenges for these technologies. Improving delivery efficiency across a broad range of cell types, as well as optimizing delivery routes in in vivo studies are also critical to harness them as advantageous tools for both research and therapy.