Ultrasound Control of Genomic Regulatory Toolboxes for Cancer Immunotherapy

Yiqian Wu (), Ziliang Huang, Yahan Liu, Peixiang He, Yuxuan Wang, Liyanran Yan, Xinhui Wang, Shanzi Gao, Xintao Zhou, Chi Woo Yoon, Kun Sun, Yinglin Situ, Phuong Ho, Yushun Zeng, Zhou Yuan, Linshan Zhu, Qifa Zhou, Yunde Zhao, Thomas Liu, Gabriel A. Kwong, Shu Chien, Longwei Liu () and Yingxiao Wang ()
Additional contact information
Yiqian Wu: University of California San Diego
Ziliang Huang: University of California San Diego
Yahan Liu: Peking University Health Science Center
Peixiang He: University of California San Diego
Yuxuan Wang: University of Southern California
Liyanran Yan: Peking University
Xinhui Wang: Peking University
Shanzi Gao: Peking University
Xintao Zhou: Peking University
Chi Woo Yoon: University of California San Diego
Kun Sun: Shenzhen Bay Laboratory
Yinglin Situ: University of California San Diego
Phuong Ho: University of California San Diego
Yushun Zeng: University of Southern California
Zhou Yuan: University of California San Diego
Linshan Zhu: University of California San Diego
Qifa Zhou: University of Southern California
Yunde Zhao: University of California San Diego
Thomas Liu: University of California San Diego
Gabriel A. Kwong: Georgia Institute of Technology & Emory University
Shu Chien: University of California San Diego
Longwei Liu: University of California San Diego
Yingxiao Wang: University of California San Diego

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract There remains a critical need for the precise control of CRISPR (clustered regularly interspaced short palindromic repeats)-based technologies. Here, we engineer a set of inducible CRISPR-based tools controllable by focused ultrasound (FUS), which can penetrate deep and induce localized hyperthermia for transgene activation. We demonstrate the capabilities of FUS-inducible CRISPR, CRISPR activation (CRISPRa), and CRISPR epigenetic editor (CRISPRee) in modulating the genome and epigenome. We show that FUS-CRISPR-mediated telomere disruption primes solid tumours for chimeric antigen receptor (CAR)-T cell therapy. We further deliver FUS-CRISPR in vivo using adeno-associated viruses (AAVs), followed by FUS-induced telomere disruption and the expression of a clinically validated antigen in a subpopulation of tumour cells, functioning as “training centers” to activate synthetic Notch (synNotch) CAR-T cells to produce CARs against a universal tumour antigen to exterminate neighboring tumour cells. The FUS-CRISPR(a/ee) toolbox hence allows the noninvasive and spatiotemporal control of genomic/epigenomic reprogramming for cancer treatment.

Date: 2024
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DOI: 10.1038/s41467-024-54477-7

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