Non-Invasive Actuation of Chemical Reactions Through Mechanochemistry and Gas Vesicle Proteins

Recent advances in molecular engineering and biomedical ultrasound provide means to apply physical effects, including mechanical stress, deep inside tissues, but limited capability to enact specific chemical processes for applications including drug delivery and non-invasive control of cellular functions. In this work, we show that mechanochemistry, chemical processes initiated by mechanical stress, can be activated with biocompatible focused ultrasound assisted by acoustically-active proteins. Previously, activation of mechanochemistry relies on ultrasound with parameters that are likely to damage tissues. Through acoustic cavitation seeded by genetically encoded, air-filled protein nanostructures called gas vesicles, polymers undergo bond cleavage at the designed, weakest position in backbones and thus release small molecular payloads, including fluorophores and therapeutic drugs by chemical cascade. The efficiency of mechanochemical activation is comparable to what has been achieved with bulk sonication, though with weaker ultrasound parameters. Focused ultrasound further enables the activation of mechanochemistry with spatial resolution in millimeter range as well as the programmable payload release kinetics. Furthermore, we demonstrate the stimulation of mechanochemistry in tissue-mimicking gels, suggesting its potential applications in remotely controlled drug release inside body. Our platform represents a novel modality for controlling chemical reactivity non-invasively in biological systems and unlocks the translational potential of polymer mechanochemistry for therapeutic and bioimaging applications.