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With the comprehensive understanding of microorganisms and the rapid advances of physiochemical engineering and bioengineering technologies, scientists are advancing rationally‐engineered bacteria as emerging drugs for treating various diseases in clinical disease management. Engineered bacteria specifically refer to advanced physiochemical or genetic technologies in combination with cutting edge nanotechnology or physical technologies, which have been validated to play significant roles in lysing tumors, regulating immunity, influencing the metabolic pathways, etc. However, there has no specific reviews that concurrently cover physiochemically‐ and genetically‐engineered bacteria and their derivatives yet, let alone their distinctive design principles and various functions and applications. Herein, the applications of physiochemically and genetically‐engineered bacteria, and classify and discuss significant breakthroughs with an emphasis on their specific design principles and engineering methods objective to different specific uses and diseases beyond cancer is described. The combined strategies for developing in vivo biotherapeutic agents based on these physiochemically‐ and genetically‐engineered bacteria or bacterial derivatives, and elucidated how they repress cancer and other diseases is also underlined. Additionally, the challenges faced by clinical translation and the future development directions are discussed. This review is expected to provide an overall impression on physiochemically‐ and genetically‐engineered bacteria and enlighten more researchers. Engineered bacteria specifically refer to advanced physiochemical or genetic modifications of diagnostic bacteria, which can compensate for the shortcomings of natural strains. After engineering, these diagnostic bacteria are encouraged to lyse tumors, regulate immunity and cellular communication such immune cells, influence metabolic pathways, withstand harsh environments, efficiently deliver cargos, reduce virulence and express exogenous proteins or molecular biosynthetic species, etc.

In the past decade, bacteria‐based cancer immunotherapy has attracted much attention in the academic circle due to its unique mechanism and abundant applications in triggering the host anti‐tumor immunity. One advantage of bacteria lies in their capability in targeting tumors and preferentially colonizing the core area of the tumor. Because bacteria are abundant in pathogen‐associated molecular patterns that can effectively activate the immune cells even in the tumor immunosuppressive microenvironment, they are capable of enhancing the specific immune recognition and elimination of tumor cells. More attractively, during the rapid development of synthetic biology, using gene technology to enable bacteria to be an efficient producer of immunotherapeutic agents has led to many creative immunotherapy paradigms. The combination of bacteria and nanomaterials also displays infinite imagination in the multifunctional endowment for cancer immunotherapy. The current progress report summarizes the recent advances in bacteria‐based cancer immunotherapy with specific foci on the applications of naive bacteria‐, engineered bacteria‐, and bacterial components‐based cancer immunotherapy, and at the same time discusses future directions in this field of research based on the present developments. Bacteria‐based cancer immunotherapy has shown significant potential in the realm of tumor therapy, mainly because of bacterial specific targeting and preferential colonization of tumors, the abundant natural antigen library of bacteria, and the great engineerability. These high‐quality properties of bacteria have been and are being researched extensively, allowing the discovering of best immunotherapies.

Host-associated microbiomes, particularly gut microbiomes, often harbor related but distinct microbial lineages, but how this diversity arises and is maintained is not well understood. A prerequisite for lineage diversification is reproductive isolation imposed by barriers to gene flow. In host-associated microbes, genetic recombination can be disrupted by confinement to different hosts, for example following host speciation, or by niche partitioning within the same host. Taking advantage of the simple gut microbiome of social bees, we explore the diversification of two groups of gut-associated bacteria, Gilliamella and Snodgrassella, which have evolved for 80 million y with honey bees and bumble bees. Our analyses of sequenced genomes show that these lineages have diversified into discrete populations with limited gene flow. Divergence has occurred between symbionts of different host species and, in some cases, between symbiont lineages within a single host individual. Populations have acquired genes to adapt to specific hosts and ecological niches; for example, Gilliamella lineages differ markedly in abilities to degrade dietary polysaccharides and to use the resulting sugar components. Using engineered fluorescent bacteria in vivo, we show that Gilliamella lineages localize to different hindgut regions, corresponding to differences in their abilities to use spatially concentrated nitrogenous wastes of hosts. Our findings show that bee gut bacteria can diversify due to isolation in different host species and also due to spatial niche partitioning within individual hosts, leading to barriers to gene flow.

Living systems, such as bacteria, yeasts, and mammalian cells, can be genetically programmed with synthetic circuits that execute sensing, computing, memory, and response functions. Integrating these functional living components into materials and devices will provide powerful tools for scientific research and enable new technological applications. However, it has been a grand challenge to maintain the viability, functionality, and safety of living components in freestanding materials and devices, which frequently undergo deformations during applications. Here, we report the design of a set of living materials and devices based on stretchable, robust, and biocompatible hydrogel–elastomer hybrids that host various types of genetically engineered bacterial cells. The hydrogel provides sustainable supplies of water and nutrients, and the elastomer is air-permeable, maintaining long-term viability and functionality of the encapsulated cells. Communication between different bacterial strains and with the environment is achieved via diffusion of molecules in the hydrogel. The high stretchability and robustness of the hydrogel–elastomer hybrids prevent leakage of cells from the living materials and devices, even under large deformations. We show functions and applications of stretchable living sensors that are responsive to multiple chemicals in a variety of form factors, including skin patches and gloves-based sensors. We further develop a quantitative model that couples transportation of signaling molecules and cellular response to aid the design of future living materials and devices.

Cancer is measured as a major threat to human life and is a leading cause of death. Millions of cancer patients die every year, although a burgeoning number of researchers have been making tremendous efforts to develop cancer medicine to fight against cancer. Owing to the complexity and heterogeneity of cancer, lack of ability to treat deep tumor tissues, and high toxicity to the normal cells, it complicates the therapy of cancer. However, bacterial derivative-mediated drug delivery has raised the interest of researchers in overcoming the restrictions of conventional cancer chemotherapy. In this review, we show various examples of tumor-targeting bacteria and bacterial derivatives for the delivery of anticancer drugs. This review also describes the advantages and limitations of delivering anticancer treatment drugs under regulated conditions employing these tumor-targeting bacteria and their membrane vesicles. This study highlights the substantial potential for clinical translation of bacterial-based drug carriers, improve their ability to work with other treatment modalities, and provide a more powerful, dependable, and distinctive tumor therapy. Graphical Abstract

Bacterial vectors showcase promising capabilities for the delivery of nucleic acids, providing a versatile platform that stands as an alternative to traditional methods and viral vectors, offering enhanced safety profiles and broader cargo capacity.Developing attenuated bacterial vectors for nucleic acid involves intricate engineering to weaken pathogenicity while preserving immunogenic properties.Engineering approaches through designing genetic circuits involving vacuole escape and controlled lysis are paving the way for more precise and effective delivery of genetic material.Engineering bacterial conjugation and the Type 4 Secretion System presents an intriguing avenue for nucleic acid delivery.Future methods, such as nanoparticle-based delivery systems, are offering improved targeting and delivery mechanisms for therapeutic nucleic acids. The demand for diverse nucleic acid delivery vectors, driven by recent biotechnological breakthroughs, offers opportunities for continuous improvements in efficiency, safety, and delivery capacity. With their enhanced safety and substantial cargo capacity, bacterial vectors offer significant potential across a variety of applications. In this review, we explore methods to engineer bacteria for nucleic acid delivery, including strategies such as engineering attenuated strains, lysis circuits, and conjugation machinery. Moreover, we explore pioneering techniques, such as manipulating nanoparticle (NP) coatings and outer membrane vesicles (OMVs), representing the next frontier in bacterial vector engineering. We foresee these advancements in bacteria-mediated nucleic acid delivery, through combining bacterial pathogenesis with engineering biology techniques, as a pivotal step forward in the evolution of nucleic acid delivery technologies. The demand for diverse nucleic acid delivery vectors, driven by recent biotechnological breakthroughs, offers opportunities for continuous improvements in efficiency, safety, and delivery capacity. With their enhanced safety and substantial cargo capacity, bacterial vectors offer significant potential across a variety of applications. In this review, we explore methods to engineer bacteria for nucleic acid delivery, including strategies such as engineering attenuated strains, lysis circuits, and conjugation machinery. Moreover, we explore pioneering techniques, such as manipulating nanoparticle (NP) coatings and outer membrane vesicles (OMVs), representing the next frontier in bacterial vector engineering. We foresee these advancements in bacteria-mediated nucleic acid delivery, through combining bacterial pathogenesis with engineering biology techniques, as a pivotal step forward in the evolution of nucleic acid delivery technologies.

Bacteria encode carbonic anhydrases (CAs, EC 4.2.1.1) belonging to three different genetic families, the α-, β-, and γ-classes. By equilibrating CO2 and bicarbonate, these metalloenzymes interfere with pH regulation and other crucial physiological processes of these organisms. The detailed investigations of many such enzymes from pathogenic and non-pathogenic bacteria afford the opportunity to design both novel therapeutic agents, as well as biomimetic processes, for example, for CO2 capture. Investigation of bacterial CA inhibitors and activators may be relevant for finding antibiotics with a new mechanism of action.

Although various ferroptosis inducers including magnetic nanoparticles (Fe3O4) and iron‐organic frameworks have been applied in cancer treatment, the mild immunogenicity, low targeting efficiency to the tumor, and poor tissue penetration have limited the therapeutic efficacy. Herein, a supramolecularly engineered conjugate between living bacteria (facultative anaerobic Salmonella typhimurium VNP20009, VNP) and cancer cell membranes‐coated Fe3O4 nanoparticles is developed for improving targeted delivery of Fe3O4 nanoparticles into the tumor tissue and for synergistic ferroptosis and immunotherapy of tumor. The enhanced ferroptosis induced by both Fe3O4 nanoparticles and the loaded ferroptosis inducing agent (sulfasalazine (SAS)) effectively inhibits tumor growth and generates immune response via immunogenic cell death (ICD). The colonization of VNP in tumors also induces adaptive immune responses and further promotes ferroptosis. Fundamentally, the supramolecular conjugate of VNP and cell membranes‐coated Fe3O4 can potentiate the therapeutic capability of each other through mutually magnifying the ferroptosis and immunotherapy, resulting in significantly enhanced antitumor effects. A supramolecularly engineered conjugate between living bacteria and cancer cell membranes‐coated Fe3O4 nanoparticles is developed for improving targeted delivery of Fe3O4 nanoparticles into the tumor tissue for synergistc ferroptosis and immunotherapy of tumor.

Abstract Recent advancements in cancer therapeutics, including targeted therapies and immunotherapies, have significantly improved treatment outcomes but remain limited by challenges such as off-target toxicity, poor penetration into deep tumor tissues, and the emergence of drug resistance. Engineered bacteria-based cancer therapies present a novel and versatile approach to address these limitations. Leveraging their ability to selectively colonize tumor microenvironments, bacteria can elicit antitumor immune responses and serve as platforms for the localized delivery of therapeutic agents. Through genetic engineering and synthetic biology, bacteria can be programmed to produce anticancer payloads tailored to clinical needs. This review highlights recent progress in the design and application of engineered bacteria for cancer therapy, emphasizing innovative strategies to enhance therapeutic delivery and efficacy. In addition, we discuss the integration of bacteria-based approaches with conventional therapies to overcome intratumor heterogeneity and improve treatment outcomes. Finally, we discuss insights from past and ongoing clinical trials of tumor-targeting bacteria, alongside challenges that must be surmounted to realize their full therapeutic promise.

Using synthetic biology techniques, bacteria have been engineered to serve as microrobots for diagnosing diseases and delivering treatments. These engineered bacteria can be used individually or in combination as microbial consortia. The components within these consortia complement each other, enhancing diagnostic accuracy and providing synergistic effects that improve treatment efficacy. The application of microbial therapies in cancer, intestinal diseases, and metabolic disorders underscores their significant potential. The impact of these therapies on the host's native microbiota is crucial, as engineered microbes can modulate and interact with the host's microbial environment, influencing treatment outcomes and overall health. Despite numerous advancements, challenges remain. These include ensuring the long‐term survival and safety of bacteria, developing new chassis microbes and gene editing techniques for non‐model strains, minimising potential toxicity, and understanding bacterial interactions with the host microbiota. This mini‐review examines the current state of engineered bacteria and microbial consortia in disease diagnosis and treatment, highlighting advancements, challenges, and future directions in this promising field. Bacteria including probiotics, genetically engineered bacteria, and microbial consortia are employed in disease diagnosis and treatment via diverse mechanisms.