Sonogenetic control of multiplexed genome regulation and base editing.

Manipulating gene expression in the human genome with high time and spatial precision is crucial for controlling cellular function and behavior. We present a precise, non-invasive, and tunable strategy for controlling the expression of multiple endogenous genes both in human cells and in animals. This new approach, utilizes non-invasive ultrasound as the input stimulus to control genome engineering process in cells and body. We engineered a hyper-efficient dCas12a and fused it to effectors including activator and base editors. Under a heat shock promoter, we demonstrate the system can be inducibly activated through thermal energy produced by ultrasound absorption. This system allows versatile thermal induction of gene activation or base editing across many cell types, including primary human T cells, and enables multiplexed gene activation using a single guide RNA array. In mouse models, localized temperature elevation guided by high-intensity focused ultrasound effectively triggers reporter gene expression in implanted cells. Our work underscores the potential of ultrasound as a clinically viable approach to enhance cell and gene-based therapies via precision genome and epigenome engineering.