Tumour priming by ultrasound mechanogenetics for CAR T therapy

Chi Woo Yoon^{1

2}, Chunyang Song³, Dung Ngo Minh Nguyen³, Xi Yu⁴, Linshan Zhu^{3

4}, Phuong Ho^{3

4}, Ziliang Huang^{3

4}, Gengxi Lu^{4

5}, Yuxuan Wang⁴, Fan Wei³, Yunjia Qu³, Ali Zamat³, Alexa Lewis³, Ruimin Chen^{4

5}, Yushun Zeng^{4

5}, Priyankan Datta⁶, Nan Sook Lee⁴, Christina Jamieson⁷, Bingfei Yu⁸, K Kirk Shung⁴, Qifa Zhou^{4

5}, Longwei Liu^{9

10}, Yingxiao Wang^{11

12}

Affiliations

¹ The Shu Chien-Gene Lay Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA. soulishguy@gmail.com.
² The Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA. soulishguy@gmail.com.
³ The Shu Chien-Gene Lay Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA.
⁴ The Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.
⁵ Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Aerospace and Mechanical Engineering, University of Southern California, Los Angeles, CA, USA.
⁷ Department of Urology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
⁸ Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ The Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA. longweil@usc.edu.
¹⁰ Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. longweil@usc.edu.
¹¹ The Shu Chien-Gene Lay Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA. ywang283@usc.edu.
¹² The Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA. ywang283@usc.edu.

PMID: 41174038
DOI: 10.1038/s41563-025-02391-8

Tumour priming by ultrasound mechanogenetics for CAR T therapy

Chi Woo Yoon et al. Nat Mater. 2025.

. 2025 Oct 31.

doi: 10.1038/s41563-025-02391-8. Online ahead of print.

Authors

Affiliations

¹ The Shu Chien-Gene Lay Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA. soulishguy@gmail.com.
² The Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA. soulishguy@gmail.com.
³ The Shu Chien-Gene Lay Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA.
⁴ The Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.
⁵ Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Aerospace and Mechanical Engineering, University of Southern California, Los Angeles, CA, USA.
⁷ Department of Urology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
⁸ Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ The Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA. longweil@usc.edu.
¹⁰ Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. longweil@usc.edu.
¹¹ The Shu Chien-Gene Lay Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA. ywang283@usc.edu.
¹² The Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA. ywang283@usc.edu.

PMID: 41174038
DOI: 10.1038/s41563-025-02391-8

Abstract

Cell-based cancer immunotherapy holds potential as a therapeutic approach, yet its application for solid tumour treatment remains challenging. Here we report a focused-ultrasound-based approach that mechanically induces the localized expression of CD19 antigen within a subpopulation of cells within solid tumours, which function as local 'training centres' to activate chimeric antigen receptor T cells. Activated chimeric antigen receptor T cells attack the whole cancer cell population near the tumour site, thus achieving cancer suppression. The system achieves targeted gene expression by integrating focused-ultrasound-triggered mechanical stimulation and the subsequent calcium response of cancer cells with a doxycycline-gated AND-logic genetic circuit, both of which need to be active for effective induction of CD19 expression. We validate the functionality of the approach in vitro, in organoids and in vivo, achieving direct control of user-designed gene expressions through FUS-mediated mechanical stimulation without the need of any cofactor, demonstrating the approach's potential as a versatile platform for precisely controllable immunotherapy. Overall, our combinatorial approach offers a focused-ultrasound-controlled remote and non-invasive priming of solid tumours for effective and safe chimeric antigen receptor T cell immunotherapy via the induced production of clinically validated antigens.

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Conflict of interest statement

Competing interests: Yingxiao Wang is scientific cofounder and consultant of Cell E&G Inc. and Acoustic Cell Therapy Inc. These financial interests do not affect the design, conduct or reporting of this research. The other authors declare no competing interests.

References

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1. Wu, Y. et al. Control of the activity of CAR-T cells within tumours via focused ultrasound. Nat. Biomed. Eng 5, 1336–1347 (2021). - PubMed - PMC - DOI

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Tumour priming by ultrasound mechanogenetics for CAR T therapy

Affiliations

Tumour priming by ultrasound mechanogenetics for CAR T therapy

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources