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.

Microbes have an immense metabolic capability and can adapt to a wide variety of environments; as a result, they share complicated relationships with cancer. The goal of microbial-based cancer therapy is to treat patients with cancers that are not easily treatable, by using tumor-specific infectious microorganisms. Nevertheless, a number of difficulties have been encountered as a result of the harmful effects of chemotherapy, radiotherapy, and alternative cancer therapies, such as the toxicity to non-cancerous cells, the inability of medicines to penetrate deep tumor tissue, and the ongoing problem of rising drug resistance in tumor cells. Due to these difficulties, there is now a larger need for designing alternative strategies that are more effective and selective when targeting tumor cells. The fight against cancer has advanced significantly owing to cancer immunotherapy. The researchers have greatly benefited from their understanding of tumor-invading immune cells as well as the immune responses that are specifically targeted against cancer. Application of bacterial and viral cancer therapeutics offers promising potential to be employed as cancer treatments among immunotherapies. As a novel therapeutic strategy, microbial targeting of tumors has been created to address the persisting hurdles of cancer treatment. This review outlines the mechanisms by which both bacteria and viruses target and inhibit the proliferation of tumor cells. Their ongoing clinical trials and possible modifications that can be made in the future have also been addressed in the following sections. These microbial-based cancer medicines have the ability to suppress cancer that builds up and multiplies in the tumor microenvironment and triggers antitumor immune responses, in contrast to other cancer medications.

There is growing interest in the role of microorganisms in human health and disease, with evidence showing that new types of biotherapy using engineered bacterial therapeutics, including bacterial derivatives, can address specific mechanisms of disease. The complex interactions between microorganisms and metabolic/immunologic pathways underlie many diseases with unmet medical needs, suggesting that targeting these interactions may improve patient treatment. Using tools from synthetic biology and chemical engineering, non-pathogenic bacteria or bacterial products can be programmed and designed to sense and respond to environmental signals to deliver therapeutic effectors. This review describes current progress in biotherapy using live bacteria and their derivatives to achieve therapeutic benefits against various diseases.

Despite significant recent progress in nanomedicine, drug delivery to solid tumors remains a formidable challenge often associated with low delivery efficiency and limited penetration of the drug in poorly vascularized regions of solid tumors. Attenuated strains of facultative anaerobes have been demonstrated to have exceptionally high selectivity to primary tumors and metastatic cancer, a good safety profile, and superior intratumoral penetration performance. However, bacteria have rarely been able to completely inhibit tumor growth in immunocompetent hosts solely by their presence in the tumor. We have developed a Nanoscale Bacteria-Enabled Autonomous Drug Delivery System (NanoBEADS) in which the functional capabilities of tumor-targeting bacteria are interfaced with chemotherapeutic-loaded nanoparticles, an approach that would amplify the therapeutic potential of both modalities. Here, we describe two biomanufacturing techniques to construct NanoBEADS by linking different bacterial species with polymeric theranostic vehicles. NanoBEADS are envisioned to significantly impact current practices in cancer theranostics through improved targeting and intratumoral transport properties.