SonoBacter: Ultrasound-guided Activation and Imaging of Engineered Bacteria for Stroma Reprogramming

细菌已经被研究用于癌症治疗，因为它们有能力产生可以攻击肿瘤的药物分子或酶，或者诱导可以帮助清除癌细胞的免疫反应。使用现有的细菌介导的癌症疗法存在许多问题，主要涉及它们的作用方式，以及在癌症组织中保留的细菌数量不足并进入血液系统引起感染的危险。我们的建议解决了这些问题，重点是重新编程肿瘤环境，而不是杀死癌细胞，包括一种方法来保留细菌注射的地方，并提供它们的按需激活。这种方法支持癌症去除的固有机制，不会导致耐药性，并且使用自然激发的化合物，可以影响实体肿瘤内非癌细胞的代谢，而不是使用高毒性的传统癌症药物。我们研究中的细菌将被改造成携带基因，这些基因可以被一个简单的化学信号激活，从而产生一种叫做类黄酮的植物化合物，这种化合物对非癌细胞有作用。化学信号分子将被包装在小颗粒中，包裹在一种材料中，在注射到体内后形成凝胶。这种凝胶还能包裹细菌，确保它们在注射部位的安全输送和保留。当超声波作用于胶囊时，颗粒会破裂并释放信号分子，从而激活细菌并启动类黄酮的生产。通过这种方式，活性物质的释放受到外部控制，可以按需启动，从而确保正确的递送位置和所需的类黄酮化合物在肿瘤中的浓度。除了细菌激活之外，超声波还可以用于成像，在植入细菌的造影剂的帮助下，使我们能够非侵入性地监测凝胶中细菌的流动性以及它们在肿瘤内的生长情况。此外，凝胶材料可以很容易地修改，使其既适合通过内窥镜针头注射，也适合术后插入肿瘤，使其迅速适用于当前的医疗实践。该研究的高潮将是在胰腺癌和肺癌的高级3D模型中评估细菌的抗癌活性，这将使细菌种群、活性化合物释放和活性评估得到优化，而无需动物试验。

Bacteria have been investigated for cancer therapies, either for their abilities to produce drug molecules or enzymes that can attack tumours, or to induce immune responses that could help remove cancer cells. There are a number of issues with the use of existing bacteria-mediated cancer therapies, primarily concerning their mode of action and the danger that insufficient number of bacteria will be retain in cancer tissue and that they enter the blood system to cause infection. Our proposal addresses these issues by focusing on reprogramming the tumour environment rather than killing cancer cells, including a means to retain the bacteria where they are injected, and providing their on-demand activation. This approach supports the innate mechanisms of cancer removal, does not lead to drug resistance and uses nature-inspired compounds that can impact the metabolism of non-cancerous cells within solid tumours rather than employing highly toxic traditional cancer drugs. The bacteria in our study will be engineered to carry genes which can be activated by a simple chemical signal to produce plant-based compounds, known as flavonoids, that have effects on non-cancerous cells. The chemical signal molecule will be packaged within small particles encased within a material that forms a gel upon injection into the body. This gel also encapsulates the bacteria and ensures their safe delivery and retention at the injection site. When ultrasound is applied to the capsule, the particles will burst and release the signal molecule, which in turn activates the bacteria and initiates the production of flavonoids. In this way, release of the active cargoes is controlled externally and can be initiated on-demand, thus ensuring the correct location of delivery and the desired in-tumour concentration of flavonoid compounds. In addition to bacterial activation, ultrasound can also be used for imaging, with the help of contrast agent programmed into the bacteria, allowing us to monitor non-invasively the mobility of the bacteria in the gel and their growth into and within the tumour. Furthermore, the gel material can be easily modified so that it is suitable either for injection via endoscopic needle or post-surgery insertion into the tumour, making it rapidly applicable to current medical practice. The culmination of the study will be evaluation of bacterial anti-cancer activity in advanced 3D models of pancreatic and lung cancer, which will enable optimisation of bacterial population, active compound release and activity assessment without animal use.