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, Yushun Zeng, Linshan Zhu, Qifa Zhou, Yunde Zhao, Thomas T. Liu, Gabriel A. Kwong, Shu Chien, Longwei Liu, Yingxiao Wang, Yingxiao Wang, Yingxiao Wang
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. There remains a critical need for precise control of CRISPR-based technologies. Here, the authors develop a focused ultrasound (FUS)-controllable CRISPR toolbox, allowing the noninvasive and spatiotemporal control of genomic/epigenomic reprogramming for cancer treatment combined with CAR-T therapy.