Spatiotemporal control of engineered bacteria to express interferon-γ by focused ultrasound for tumor immunotherapy

Abstract

Bacteria-based tumor therapy has recently attracted wide attentions due to its unique capability in targeting tumors and preferentially colonizing the core area of the tumor. Various therapeutic genes are also harbored into these engineering bacteria to enhance their anti-tumor efficacy. However, it is difficult to spatiotemporally control the expression of these inserted genes in the tumor site. Here, we engineer an ultrasound-responsive bacterium (URB) which can induce the expression of exogenous genes in an ultrasound-controllable manner. Owing to the advantage of ultrasound in tissue penetration, an acoustic remote control of bacterial gene expression can be realized by designing a temperature-actuated genetic switch. Cytokine interferon-γ (IFN-γ), an important immune regulatory molecule that plays a significant role in tumor immunotherapy, is used to test the system. Our results show that brief hyperthermia induced by focused ultrasound promotes the expression of IFN-γ gene, improving anti-tumor efficacy of URB in vitro and in vivo. Our study provides an alternative strategy for bacteria-mediated tumor immunotherapy.

MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation

“…Engineered bacteria can achieve targeted gene reprogramming, selective functional recombination and precise space-time control, so they are widely used in medical and pharmaceutical industries ( 40 ). Genetically engineered bacteria have been developed as diagnostic and therapeutic tools for the treatment of many diseases, including cancer ( 41 ), diabetes ( 38 ), inflammatory bowel disease ( 42 , 43 ) and viral infection ( 44 ). Chen Zhiyi of Nanhua University and others designed a kind of ultrasound-responsive bacteria, which can induce the expression of foreign gene IFN-γ in an ultrasound-controlled way, and improve the anti-tumor efficacy of the engineering bacteria in vitro and in vivo ( 42 ).…”

“…Genetically engineered bacteria have been developed as diagnostic and therapeutic tools for the treatment of many diseases, including cancer ( 41 ), diabetes ( 38 ), inflammatory bowel disease ( 42 , 43 ) and viral infection ( 44 ). Chen Zhiyi of Nanhua University and others designed a kind of ultrasound-responsive bacteria, which can induce the expression of foreign gene IFN-γ in an ultrasound-controlled way, and improve the anti-tumor efficacy of the engineering bacteria in vitro and in vivo ( 42 ). AmirZarrinpar of the University of California genetically engineered natural E. coli isolated from the intestines of mice to express specific genes and improve diabetes ( 38 ).…”

Research progress of stimuli-responsive ZnO-based nanomaterials in biomedical applications

“…On the contrary, ultrasound with high tissue penetration overcomes the critical problem of penetration depth limitation, making it possible to monitor and treat deep diseases. 80 Studies have shown that ZnO NPs are ideal biocompatible ultrasound contrast agents. For instance, a novel type of implantable passive sensor for mechanical properties of biological tissues was constructed by embedding ZnO NPs into polydimethylacrylamide nanocomposite hydrogels, which was able to operate with large linear ultrasonic sensitivity and cover the strain monitoring of soft tissue and hard tissue, realizing remote assessment of organ deformation after implantation.…”

Awareness of intratumoral bacteria and their potential application in cancer treatment

“…This system has been used to control the expression of interferon-γ (IFN-γ) by bacteria in tumors with ultrasound, and has been successfully applied to immunotherapy of subcutaneous transplanted breast cancer and in situ transplanted liver cancer with good results. It has great potential applications in the regulation of gene expression in living cells such as bacteria, immune cells and stem cells [ 83 ].…”