Ultrasound Control of Genomic Regulatory Toolboxes for Cancer Immunotherapy
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.
Authors
- Yushun Zeng (ORCID: https://orcid.org/0000-0001-5995-4085)
- Yunde Zhao (ORCID: https://orcid.org/0000-0002-7224-8449)
- Longwei Liu (ORCID: https://orcid.org/0000-0003-4229-9066)
- Yiqian Wu (ORCID: https://orcid.org/0000-0002-6313-6015)
- Yingxiao Wang (ORCID: https://orcid.org/0000-0003-0265-326X)
- Thomas T. Liu (ORCID: https://orcid.org/0000-0002-1978-7486)
- Shu Chien (ORCID: https://orcid.org/0000-0003-0332-285X)
- Yuan Zhou (ORCID: https://orcid.org/0000-0003-4413-7490)
- Liyanran Yan (ORCID: https://orcid.org/0000-0003-4352-048X)
- Kun Sun (ORCID: https://orcid.org/0000-0002-9883-1616)
- Qifa Zhou (ORCID: https://orcid.org/0000-0003-1527-3020)
- Yinglin Situ (ORCID: https://orcid.org/0009-0007-3810-2626)
- Gabriel A. Kwong (ORCID: https://orcid.org/0000-0002-6255-6755)
- Ziliang Huang (ORCID: https://orcid.org/0000-0002-4102-3300)
- Xintao Zhou
- Xinhui Wang (ORCID: https://orcid.org/0000-0002-4109-5793)
- Yuxuan Wang (ORCID: https://orcid.org/0000-0003-1135-3605)
- Yahan Liu (ORCID: https://orcid.org/0000-0002-5948-4615)
- Phuong Ho (ORCID: https://orcid.org/0009-0003-6124-4834)
- Linshan Zhu (ORCID: https://orcid.org/0009-0005-0892-3998)
- Chi Woo Yoon (ORCID: https://orcid.org/0000-0003-4619-7083)
- Shanzi Gao
- Peixiang He
Institutions
- University of Southern California (US)
- Georgia Institute of Technology (US)
- Peking University (CN)
- The Wallace H. Coulter Department of Biomedical Engineering (US)
- University of California San Diego (US)
- Shenzhen Bay Laboratory (CN)
- La Jolla Bioengineering Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1038/s41467-024-54477-7
- Citations
- 22
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 5.14
Funders
- National Institutes of Health
- National Eye Institute
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke