Sonogenetics-controlled synthetic designer cells for cancer therapy in tumor mouse models

Tian Gao; Lingxue Niu; Xin Wu; Di Dai; Yang Zhou; Mengyao Liu; Ke Wu; Yuanhuan Yu; Ningzi Guan; Haifeng Ye

doi:10.1016/j.xcrm.2024.101513

Sonogenetics-controlled synthetic designer cells for cancer therapy in tumor mouse models

Cell Rep Med. 2024 Apr 5:101513. doi: 10.1016/j.xcrm.2024.101513. Online ahead of print.

Authors

Tian Gao¹, Lingxue Niu¹, Xin Wu², Di Dai¹, Yang Zhou³, Mengyao Liu¹, Ke Wu¹, Yuanhuan Yu¹, Ningzi Guan⁴, Haifeng Ye⁵

Affiliations

¹ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
² Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China; The Radiology Department of Shanxi Provincial People's Hospital, The Fifth Hospital of Shanxi Medical University, Taiyuan 030001, China.
³ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China; Wuhu Hospital, Health Science Center, East China Normal University, Middle Jiuhua Road 263, Wuhu City, China.
⁴ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China. Electronic address: nzguan@bio.ecnu.edu.cn.
⁵ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China; Wuhu Hospital, Health Science Center, East China Normal University, Middle Jiuhua Road 263, Wuhu City, China. Electronic address: hfye@bio.ecnu.edu.cn.

PMID: 38608697
DOI: 10.1016/j.xcrm.2024.101513

Abstract

Bacteria-based therapies are powerful strategies for cancer therapy, yet their clinical application is limited by a lack of tunable genetic switches to safely regulate the local expression and release of therapeutic cargoes. Rapid advances in remote-control technologies have enabled precise control of biological processes in time and space. We developed therapeutically active engineered bacteria mediated by a sono-activatable integrated gene circuit based on the thermosensitive transcriptional repressor TlpA₃₉. Through promoter engineering and ribosome binding site screening, we achieved ultrasound (US)-induced protein expression and secretion in engineered bacteria with minimal noise and high induction efficiency. Specifically, delivered either intratumorally or intravenously, engineered bacteria colonizing tumors suppressed tumor growth through US-irradiation-induced release of the apoptotic protein azurin and an immune checkpoint inhibitor, a nanobody targeting programmed death-ligand 1, in different tumor mouse models. Beyond developing safe and high-performance designer bacteria for tumor therapy, our study illustrates a sonogenetics-controlled therapeutic platform that can be harnessed for bacteria-based precision medicine.

Keywords: PD-L1 nb; TlpA39; VNP20009; azurin; bacteria-based therapy; cancer therapy; sonogenetics; synthetic designer cells; synthetic gene circuit; ultrasound.