Engineered Bacteria-Based Living Materials for Biotherapeutic Applications

Abstract

Future advances in therapeutics demand the development of dynamic and intelligent living materials. The past static monofunctional materials shall be unable to meet the requirements of future medical development. Also, the demand for precision medicine has increased with the progressively developing human society. Therefore, engineered living materials (ELMs) are vitally important for biotherapeutic applications. These ELMs can be cells, microbes, biofilms, and spores, representing a new platform for treating intractable diseases. Synthetic biology plays a crucial role in the engineering of these living entities. Hence, in this review, the role of synthetic biology in designing and creating genetically engineered novel living materials, particularly bacteria, has been briefly summarized for diagnostic and targeted delivery. The main focus is to provide knowledge about the recent advances in engineered bacterial-based therapies, especially in the treatment of cancer, inflammatory bowel diseases, and infection. Microorganisms, particularly probiotics, have been engineered for synthetic living therapies. Furthermore, these programmable bacteria are designed to sense input signals and respond to disease-changing environments with multipronged therapeutic outputs. These ELMs will open a new path for the synthesis of regenerative medicines as they release therapeutics that provide in situ drug delivery with lower systemic effects. In last, the challenges being faced in this field and the future directions requiring breakthroughs have been discussed. Conclusively, the intent is to present the recent advances in research and biomedical applications of engineered bacteria-based therapies during the last 5 years, as a novel treatment for uncontrollable diseases.

Applications of Bacteria Decorated with Synthetic DNA Constructs

“…The unique properties of bacteria, such as their ability to generate their own matrix (e.g., biofilms), catalyze reactions, produce small molecules, as well as their amenability to chemical and genetic engineering, have made them particularly attractive candidates for developing such systems. For example, organized bacterial assemblies have been used in wound healing, [ 24 ] tissue‐engineering, [ 25 ] drug delivery, [ 13a ] and in developing energy‐producing devices. [ 26 ] Next, we discuss the ways by which DNA constructs have been used to assemble well‐defined bacterial architectures and the potential application of such a microfabrication.…”

“…For example, the engineering of bacterial cell surfaces is considered a promising strategy for the future treatment of diseases or for generating living materials and devices. [ 13 ] The potential advantages of modifying the surfaces of bacteria over human cells include the simplicity by which bacteria can be genetically engineered, as well as the various unique structural elements that can be functionalized on their surfaces, such as peptidoglycans, d ‐amino acids, glycoproteins, and lipopolysaccharides. The methods by which bacterial surfaces can be modified through genetic engineering, [ 14 ] as well as by metabolic [ 15 ] and enzymatic [ 10 ] modifications have been adequately summarized in other reviews.…”

Engineering bacteria to modulate host metabolism

“…Moreover, host baseline characteristics and microbiome composition are the main drivers of the different colonization patterns of probiotics 22 that should be taken into consideration in order to provide long‐term, autonomous, and efficient therapies. For a stable engraftment that will provide a significant and durable metabolic effect, they may need concomitant antibiotic treatment, in order to allow their implantation, or multiple administrations to induce a positive pressure at the gut level 8 . Moreover, factors such as abundance, degree of colonization, and interaction with the immune system vary widely between strains and could be critical for the successful implementation of a given application 9 .…”

“…Once the strain is implanted, the robustness of engineered functions to time and changing environments must be high and is a major challenge to long‐term cellular therapies 5 . Finally, engineered bacteria may be very expensive, particularly if complex genetic editing is involved, and this would limit their translation into clinical practice 8 . Once all these technical challenges are resolved, and for the product to be used by humans, it must feature a positive benefit–risk ratio.…”

“…With the increasing understanding of how the microbiota modulates diseases, these engineered microorganisms gained particular interest as they can target specific functions of the microbiota that are impaired in disease and restore them. Microorganisms can be reprogrammed to perform complex tasks by using different genetic approaches and circuits 8 . They can also be designed to express functions that address monogenic inborn errors of metabolism (e.g., phenylalanine metabolism in patients with phenylketonuria) 10,11 and other orphan diseases.…”