Remote Control of Eukaryotic Gene Expression by a Modular Ultrasound‐Responsive RNA Toolkit

Abstract Achieving remote control of biological processes remains a significant challenge in genetics. Although ultrasound has been employed to remotely regulate biological functions by targeting mechanosensitive ion channels, existing systems are constrained by the limited responsiveness of specific channels to specific ultrasound frequencies and their applicability to only a few cell types. Sonogenetics has shown promise for promoter control, thereby regulating gene transcription in eukaryotes. Here, we introduce a new modular toolkit for regulating gene expression using ultrasound‐responsive RNA carriers capable of releasing small molecule modulators in response to a broad spectrum of ultrasound frequencies. The cells contain engineered mRNA structures encoding riboswitches or aptazymes, which respond specifically to these small molecule modulators finally controlling downstream protein expression by biocompatible ultrasound. This toolkit is versatile, functioning across various eukaryotic systems—from yeast to mammalian cells—and offers control over gene expression by regulating mRNA translation. We demonstrated that this sonogenetic toolkit robustly modulates gene expression, achieving up to a six‐fold downregulation of protein levels in response to ultrasound stimulation. By expanding the application of sonogenetics across eukaryotes, this RNA‐based toolkit might provide a promising platform for remotely controlling protein function in specific tissues through on‐demand ultrasound activation in the future.