Sono-Mechanogenetics: Linking Ultrasound Physics With Cellular Mechanobiology.

Sono-mechanogenetics aims to achieve remote, noninvasive control of cellular behavior by coupling focused ultrasound with genetically specified biological responses mediated through mechanotransduction pathways. Although recent studies have demonstrated diverse proof-of-concept applications, progress in the field has largely emphasized actuator discovery and application-driven demonstrations, often treating ultrasound as a black-box stimulus and mechanosensitive elements as isolated sensors. In this review, we seek to reframe sono-mechanogenetics through the combined lenses of ultrasound physics and cellular mechanobiology. We first describe how ultrasound delivers programmable mechanical energy through distinct deformation modes, and how these physical inputs intersect with biological force-sensing networks. We then outline core mechanotransduction pathways spanning the extracellular matrix (ECM), membrane, cytoskeleton, and nucleus, and discuss how these systems naturally sense, integrate, and transduce mechanical information. Building on this foundation, we specifically introduce current applications in neural modulation and immunotherapy, emphasizing the underlying mechanical perturbations rather than application-specific outcomes. Finally, we discuss practical constraints and future directions, highlighting how mechanobiological principles can guide the rational design of next-generation sono-mechanogenetic systems. Together, this review aims to provide a focused overview of the field from empirical activation toward mechanistically informed and predictive control.