Non-invasive actuation of chemical reactions through mechanochemistry and gas vesicle proteins

Introduction:: 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.


Materials and Methods:: Previously, activation of mechanochemistry, a chemical process triggered by mechanical stress, has relied on ultrasound with parameters that may damage tissues. Here, utilizing genetically encoded, air-filled protein nanostructures called gas vesicles as acoustic cavitation nuclei, we realize acoustic cavitation and thereby induce mechanochemistry with biocompatible ultrasound parameters. We further implement polymer design so that the mechanochemistry can cleave specific chemical bonds in backbones and trigger the localized release of small molecule payloads through a chemical cascade.


Results, Conclusions, and Discussions:: Focused ultrasound at 330 kHz and 1.46 MPa peak negative pressure in the presence of gas vesicles is sufficient to induce mechanochemical bond scission in a polymer mechanophore and release small molecule payloads, with similar efficiency achieved by bulk sonication. This is evidenced by a decrement in the molecular weight of the polymer and the activation of fluorescence upon chemical transformation. A cavitation-based mechanism is supported by passive cavitation mapping. Furthermore, the mechanochemical process can be activated in tissue-mimicking gels with spatial resolution in the millimeter range, suggesting its potential applications in remotely controlled, long-lasting drug release inside the body.

We have demonstrated that biocompatible ultrasound can actuate designed mechanochemistry processes through gas vesicle-seeded acoustic cavitation. The non-invasive actuation of chemistry reactions may enable applications in remotely controlled, long-lasting drug release.




Acknowledgements (Optional): : This research is supported by the Packard Foundation and Resnick Sustainability Institute at Caltech.

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