Regulatable in vivo gene expression via adaptamers

Precise, reversible control of transgene expression is essential for safe and durable gene therapy, yet current inducible systems remain difficult to translate in vivo due to large size, limited induction duration, and dependence on immunogenic regulators. Here, we present the adaptamer (adenosine deaminases acting on RNA [ADAR]-modulatable aptamer), a compact (<120 base pair) RNA switch that couples FDA-approved small-molecule-responsive aptamers with endogenous ADAR-mediated RNA editing to regulate expression. Ligand binding stabilizes a double-stranded RNA structure that recruits ADAR to convert a stop codon into a sense codon, restoring downstream protein translation. This cleavage-free, post-transcriptional mechanism enables precise, small-molecule-dependent modulation without exogenous protein machinery. We demonstrate that adaptamers are highly functional across multiple cell lines, including human T cells. In mice, adeno-associated virus (AAV)-delivered adaptamer-controlled FGF21 expression induced metabolic remodeling, reversing obesity and hepatic steatosis. This minimal, programmable system offers a clinically compatible approach for tunable genetic medicines and safe deployment of pleiotropic and dose-limited proteins.