Abstract:Background
Recently, bacterial extracellular vesicles (EVs) have been considered to play crucial roles in various biological processes and have great potential for developing cancer therapeutics and biomedicine. However, studies on bacterial EVs have mainly focused on outer membrane vesicles released from gram-negative bacteria since the outermost peptidoglycan layer in gram-positive bacteria is thought to preclude the release of EVs as a physical barrier.
Results… Show more
Bacterial extracellular vesicles (BEVs) are non-replicative nanostructures released by Gram-negative and Gram-positive bacteria as a survival mechanism and inter- and intraspecific communication mechanism. Due to BEVs physical, biochemical, and biofunctional characteristics, there is interest in producing and using them in developing new therapeutics, vaccines, or delivery systems. However, BEV release is typically low, limiting their application. Here, we provide a biotechnological perspective to enhance BEV production, highlighting current strategies. The strategies include the production of hypervesiculating strains through gene modification, bacteria culture under stress conditions, and artificial vesicles production. We discussed the effect of these production strategies on BEVs types, morphology, composition, and activity. Furthermore, we summarized general aspects of BEV biogenesis, functional capabilities, and applications, framing their current importance and the need to produce them in abundance. This review will expand the knowledge about the range of strategies associated with BEV bioprocesses to increase their productivity and extend their application possibilities.
Graphical abstract
Bacterial extracellular vesicles (BEVs) are non-replicative nanostructures released by Gram-negative and Gram-positive bacteria as a survival mechanism and inter- and intraspecific communication mechanism. Due to BEVs physical, biochemical, and biofunctional characteristics, there is interest in producing and using them in developing new therapeutics, vaccines, or delivery systems. However, BEV release is typically low, limiting their application. Here, we provide a biotechnological perspective to enhance BEV production, highlighting current strategies. The strategies include the production of hypervesiculating strains through gene modification, bacteria culture under stress conditions, and artificial vesicles production. We discussed the effect of these production strategies on BEVs types, morphology, composition, and activity. Furthermore, we summarized general aspects of BEV biogenesis, functional capabilities, and applications, framing their current importance and the need to produce them in abundance. This review will expand the knowledge about the range of strategies associated with BEV bioprocesses to increase their productivity and extend their application possibilities.
Graphical abstract
“…Until recently, research on bEVs has mostly concentrated on outer membrane vesicles generated by gram-negative bacteria by membrane blebbing. Gram-positive bacteria, which lack an outer membrane, were initially thought likely to be incapable of EV release due to their strong peptidoglycan cell walls [ 51 ]. A renewed focus on the formation of these vesicles has been sparked by the discovery of physiologically active EVs in gram-positive bacteria in more recent investigations [ 51 – 53 ].…”
Section: Microbiome Revelations Spur Interest In Bugs-as-drugs For Ca...mentioning
confidence: 99%
“…Gram-positive bacteria, which lack an outer membrane, were initially thought likely to be incapable of EV release due to their strong peptidoglycan cell walls [ 51 ]. A renewed focus on the formation of these vesicles has been sparked by the discovery of physiologically active EVs in gram-positive bacteria in more recent investigations [ 51 – 53 ]. Structural variations between gram-negative and gram-positive bacteria induce distinct EV biogenesis pathways.…”
Section: Microbiome Revelations Spur Interest In Bugs-as-drugs For Ca...mentioning
There are a growing number of studies linking the composition of the human microbiome to disease states and treatment responses, especially in the context of cancer. This has raised significant interest in developing microbes and microbial products as cancer immunotherapeutics that mimic or recapitulate the beneficial effects of host-microbe interactions. Bacterial extracellular vesicles (bEVs) are nano-sized, membrane-bound particles secreted by essentially all bacteria species and contain a diverse bioactive cargo of the producing cell. They have a fundamental role in facilitating interactions among cells of the same species, different microbial species, and even with multicellular host organisms in the context of colonization (microbiome) and infection. The interaction of bEVs with the immune system has been studied extensively in the context of infection and suggests that bEV effects depend largely on the producing species. They thus provide functional diversity, while also being nonreplicative, having inherent cell-targeting qualities, and potentially overcoming natural barriers. These characteristics make them highly appealing for development as cancer immunotherapeutics. Both natively secreted and engineered bEVs are now being investigated for their application as immunotherapeutics, vaccines, drug delivery vehicles, and combinations of the above, with promising early results. This suggests that both the intrinsic immunomodulatory properties of bEVs and their ability to be modified could be harnessed for the development of next-generation microbe-inspired therapies. Nonetheless, there remain major outstanding questions regarding how the observed preclinical effectiveness will translate from murine models to primates, and humans in particular. Moreover, research into the pharmacology, toxicology, and mass manufacturing of this potential novel therapeutic platform is still at early stages. In this review, we highlight the breadth of bEV interactions with host cells, focusing on immunologic effects as the main mechanism of action of bEVs currently in preclinical development. We review the literature on ongoing efforts to develop natively secreted and engineered bEVs from a variety of bacterial species for cancer therapy and finally discuss efforts to overcome outstanding challenges that remain for clinical translation.
“…The production of extracellular vesicles (EVs) by Gram‐positive bacteria was investigated by STORM. The results showed that EV can be formed by membrane blebbing and explosive cell lysis, suggesting that cell wall degradation plays a significant role in their biogenesis (Jeong et al., 2022). SIM of fluorescently labeled teixobactin, a recently introduced antibiotic, allowed visualization of teixobactin interactions and structural organization in the Gram‐positive cell wall.…”
Section: Cell Wall and Membrane Processesmentioning
Super‐resolution fluorescence microscopy technologies developed over the past two decades have pushed the resolution limit for fluorescently labeled molecules into the nanometer range. These technologies have the potential to study bacterial structures, for example, macromolecular assemblies such as secretion systems, with single‐molecule resolution on a millisecond time scale. Here we review recent applications of super‐resolution fluorescence microscopy with a focus on bacterial secretion systems. We also describe MINFLUX fluorescence nanoscopy, a relatively new technique that promises to one day produce molecular movies of molecular machines in action.
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