Bacteria can be genetically engineered to act as therapeutic delivery vehicles in the treatment of tumors, killing cancer cells or activating the immune system. This is known as bacteria-mediated cancer therapy (BMCT). Tumor invasion, colonization and tumor regression are major biological events, which are directly associated with antitumor effects and are uncontrollable due to the influence of tumor microenvironments during the BMCT process. Here, we developed a genetic circuit for dynamically programming bacterial lifestyles (planktonic, biofilm or lysis), to precisely manipulate the process of bacterial adhesion, colonization and drug release in the BMCT process, via hierarchical modulation of the lighting power density of near-infrared (NIR) light. The deep tissue penetration of NIR offers us a modality for spatio-temporal and non-invasive control of bacterial genetic circuits in vivo. By combining computational modeling with a high-throughput characterization device, we optimized the genetic circuits in engineered bacteria to program the process of bacterial lifestyle transitions by altering the illumination scheme of NIR. Our results showed that programming intratumoral bacterial lifestyle transitions allows precise control of multiple key steps throughout the BMCT process and therapeutic efficacy can be greatly improved by controlling the localization and dosage of therapeutic agents via optimizing the illumination scheme.
细菌可通过基因工程改造，成为肿瘤治疗中的治疗性递送载体，通过杀死癌细胞或激活免疫系统发挥作用。这种方法被称为细菌介导癌症疗法。肿瘤侵袭、定植和消退是三个主要的生物学事件，它们直接与抗肿瘤效应相关，并在细菌介导癌症治疗过程中受肿瘤微环境影响而难以控制。本研究通过建立基因电路，借助近红外光光照功率密度的分级调控，实现了对细菌生活方式（浮游、生物膜形成或裂解）的动态编程，从而精准操控细菌介导癌症治疗过程中的细菌黏附、定植及药物释放。近红外光的深部组织穿透能力为我们提供了一种在体内实现时空特异性、非侵入性控制细菌基因电路的手段。通过将计算建模与高通量表征设备相结合，我们优化了工程菌中的基因电路，通过改变近红外光照射方案来编程细菌生活方式的转换过程。研究结果显示，编程肿瘤内细菌生活方式的转换能够精确控制细菌介导癌症治疗过程中的多个关键步骤，并通过优化光照方案调控治疗药物的定位与剂量，从而显著提升治疗效果。
Programming the lifestyles of engineered bacteria for cancer therapy
肿瘤(癌症)患者之家