PDF(Pubmed)
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.
摘要：
基于细菌的疗法是癌症治疗的有力策略，然而，由于缺乏可调节的遗传开关来安全地调节治疗药物的局部表达和释放，它们的临床应用受到限制。远程控制技术的快速发展使得能够在时间和空间上精确控制生物过程。我们基于热敏转录阻遏物TlpA39开发了由可激活的整合基因电路介导的治疗活性工程细菌。通过启动子工程和核糖体结合位点筛选,我们以最小的噪声和高的诱导效率实现了超声（US）诱导的工程菌蛋白表达和分泌。具体来说,肿瘤内或静脉内递送，通过US辐射诱导的凋亡蛋白天青蛋白和免疫检查点抑制剂的释放，工程细菌定植肿瘤抑制了肿瘤的生长，在不同的肿瘤小鼠模型中，靶向程序性死亡配体1的纳米抗体。除了开发用于肿瘤治疗的安全和高性能设计细菌，我们的研究说明了一个由超声遗传学控制的治疗平台,该平台可用于基于细菌的精准医学.
