Acoustically triggered mechanotherapy using genetically encoded gas vesicles

Recent advances in molecular engineering and synthetic biology provide biomolecular and cell-based therapies with a high degree of molecular specificity, but limited spatiotemporal control. Here we show that biomolecules and cells can be engineered to deliver potent mechanical effects at specific locations inside the body through ultrasound-induced inertial cavitation. This capability is enabled by gas vesicles, a unique class of genetically encodable air-filled protein nanostructures. We show that low-frequency ultrasound can convert these biomolecules into micrometre-scale cavitating bubbles, unleashing strong local mechanical effects. This enables engineered gas vesicles to serve as remotely actuated cell-killing and tissue-disrupting agents, and allows genetically engineered cells to lyse, release molecular payloads and produce local mechanical damage on command. We demonstrate the capabilities of biomolecular inertial cavitation in vitro, in cellulo and in vivo, including in a mouse model of tumour-homing probiotic therapy. Gas vesicles are air-filled protein nanostructures naturally expressed by certain bacteria and archaea to achieve cellular buoyancy. Here the authors show that, under the stimulation of pulsed ultrasound, targeted gas vesicles and gas vesicles expressed in genetically modified bacteria and mammalian cells release nanobubbles that, collapsing, lead to controlled mechanical damage of the surrounding biological milieu, demonstrating that, under focused ultrasound actuation, gas vesicles have potential applications as therapeutic agents.