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Published December 2021 | public
Journal Article Open

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.

Additional Information

© 2021 Nature Publishing Group. Received 12 July 2020; Accepted 03 August 2021; Published 27 September 2021. The authors thank D. Piraner, A. Lakshmanan, A. Farhadi and P. Ramesh for helpful discussions. In addition, we thank A. Farhadi for his help with the GvpC-RGD variant and H. Davis for his inputs on the optical design of the high-speed set-up. We thank M. Harel (www.maayanillustration.com) for the illustrations in this paper. We also thank A. McDowall for help with electron microscopy and C. Rabut for help with the animal experiments. This project was supported by the David and Lucile Packard Fellowship for Science and Engineering (M.G.S.) and the Heritage Medical Research Institute (M.G.S.). In addition, this project received funding from the European Union's Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 792866 (A.B.-Z.). A.B.-Z. was also supported by the Lester Deutsch Fellowship. A.N. was supported by the Amgen scholars programme. S.S. is supported by the NSF Graduate Research Fellowship. M.H.A. is supported by the NSF Graduate Research Fellowship and the P.D. Soros Fellowship. M.T.B. is supported by the NSF Graduate Research Fellowship. D. Maresca is supported by the Human Frontiers Science Program Cross-Disciplinary Fellowship. Data availability: Plasmids sequences are given in Supplementary Table 3, and will be made available through Addgene. All the raw data related to the plots and graphs are available at https://github.com/shapiro-lab/GV_cavitation.git. All the other materials and data are available from the corresponding author upon reasonable request. Code availability: MATLAB codes are available from the corresponding author upon reasonable request. Author Contributions: A.B.-Z. and M.G.S. conceived the study. A.B.-Z., A.N., D. Maresca, D.R.M., S.Y. and S.S. designed, planned and conducted the in vitro experiments. A.B.-Z., A.N., M.T.B., R.C.H., A.L.-G. and M.B.S. designed, planned and conducted in vivo experiments. A.B.-Z. edited the gene circuits with the guidance of M.H.A. A.B.-Z., A.N., D.R.M., S.Y. and D. Maresca analysed the data. D. Malounda prepared the purified GVs. All the authors discussed the results. A.B.-Z., A.N. and M.G.S wrote the manuscript with input from all the authors. All the authors have given their approval for the final version of the manuscript. M.G.S. supervised the research. Competing interests: The California Institute of Technology has filed a patent application related to this manuscript. The authors have no other competing interests. Peer review information: Nature Nanotechnology thanks Mark Borden and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Attached Files

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Additional details

September 22, 2023
September 22, 2023