Bacteria extracellular vesicle as nanopharmaceuticals for versatile biomedical potential

Ho, Ming Yao; Liu, Songhan; **ng, Bengang

doi:10.1186/s40580-024-00434-5

Bacteria extracellular vesicle as nanopharmaceuticals for versatile biomedical potential

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Published: 11 July 2024

Volume 11, article number 28, (2024)
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Bacteria extracellular vesicle as nanopharmaceuticals for versatile biomedical potential

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Ming Yao Ho¹^na1,
Songhan Liu¹^na1 &
Bengang **ng¹

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Abstract

Bacteria extracellular vesicles (BEVs), characterized as the lipid bilayer membrane-surrounded nanoparticles filled with molecular cargo from parent cells, play fundamental roles in the bacteria growth and pathogenesis, as well as facilitating essential interaction between bacteria and host systems. Notably, benefiting from their unique biological functions, BEVs hold great promise as novel nanopharmaceuticals for diverse biomedical potential, attracting significant interest from both industry and academia. Typically, BEVs are evaluated as promising drug delivery platforms, on account of their intrinsic cell-targeting capability, ease of versatile cargo engineering, and capability to penetrate physiological barriers. Moreover, attributing to considerable intrinsic immunogenicity, BEVs are able to interact with the host immune system to boost immunotherapy as the novel nanovaccine against a wide range of diseases. Towards these significant directions, in this review, we elucidate the nature of BEVs and their role in activating host immune response for a better understanding of BEV-based nanopharmaceuticals’ development. Additionally, we also systematically summarize recent advances in BEVs for achieving the target delivery of genetic material, therapeutic agents, and functional materials. Furthermore, vaccination strategies using BEVs are carefully covered, illustrating their flexible therapeutic potential in combating bacterial infections, viral infections, and cancer. Finally, the current hurdles and further outlook of these BEV-based nanopharmaceuticals will also be provided.

Graphical Abstract

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1 Introduction

Vesiculation is a crucial and fundamental process across all kinds of species to produce the extracellular vesicles that serve as essential mediators of basic physiological events [1]. These nanovesicles are filled with molecular patterns originated from parent cells, including metabolites, nucleic acids, proteins, and signaling molecules, to maintain cell growth and homeostasis [2, 3]. Biological regulation by extracellular vesicles is widespread across both prokaryotes and eukaryotes [4]. Notably, bacteria, as one of the major inhabitants in the human body, establish intricate relationships with host health and disease, wherein bacterial extracellular vesicles (BEVs) are indispensably involved in these processes [5, 6]. With the increasing and deep understanding of their biological function, BEVs are found to influence various cellular behaviors, including the transport of genetic information, phage infection, mediation of metabolism, as well as interaction between bacteria-bacteria and bacteria-host [7, 8].

Particularly, BEVs are characterized as nanosized nanoparticles, surrounded by lipid-bilayer membranes, ranging from 20 to 400 nm in diameter [7]. In account of the diversity of bacterial types and biogenesis mechanisms, the BEVs could carry versatile cargos inherited from mother cells, such as lipopolysaccharides (LPS), endotoxins, genetic information, cytosolic and membrane proteins [9]. By thanking the unique structure and intrinsic properties of BEVs, these naturally occurring nanovesicles attract the research interest to be developed as novel nanopharmaceuticals, prompting further exploration of their biomedical applications [Full size image

2 Biogenesis mechanism of diverse bacteria-derived extracellular vesicles

Bacterial extracellular vesicles (BEVs) are crucial biological components mediating the bacteria's cellular events, including nutrient acquisition, genetic information transfer, and mediation of interaction with host cells [7]. All these functions suggest that BEVs exhibit great potential as novel nanopharmaceuticals to combat diverse diseases and regulate healthcare. As a fundamental biological process of living matter, BEVs are produced from parent bacteria by a spontaneous process without additional energy consumption [24]. Thus, a detailed understanding of the structure, composition, biogenesis, and functions of BEVs boosts the development of these naturally-produced membrane entities for biomedical applications, especially as drug delivery platforms and vaccination strategies.

Due to the different types of parent bacteria, including Gram-negative and Gram-positive strains, the diverse biogenesis mechanisms lead to the unique membrane structure and loaded contents of distinct BEV types. Typically, Gram-negative bacteria have a double-layered membrane structure, comprised of the outer membrane, periplasmic space, and cytoplasmic membrane, while Gram-positive bacteria have only one cytoplasmic membrane covered by a thick cell wall of peptidoglycan [25]. The various formation mechanisms and characteristics of BEVs are attributed to their original bacteria as shown in Fig. 2.

The extracellular vesicles derived from Gram-negative bacteria have two main models of their biogenesis mechanism, including blebbing of the outer membrane and explosive cell lysis. When the cell envelopes suffer from abnormal disturbances (e.g. hydrophobic compound interaction, instability of peptidoglycan biosynthesis, denaturation of membrane protein, etc.), the outer membrane will undergo the blebbing to produce the outer membrane vesicles (OMVs) [7, 9]. During this progress, the inner membrane remains intact to prevent loading the cytoplasmic cargo into the OMVs. The size of OMVs is around 20–250 nm with spherical morphology, containing abundant lipopolysaccharides (LPS), lipids, and membrane proteins [24, 26]. On the other hand, when the peptidoglycan layer of Gram-negative bacteria is weakened by autolysin, the inner membrane will subsequently protrude into the periplasm to produce the outer-inner membrane vesicles (OIMVs). Similarly, the explosive outer membrane vesicles (EOMVs) were produced by the model of explosive cell death model [7, 27, 28]. The phage-derived endolysin destroys the peptidoglycan layer around the bacteria, inducing the cell explosion and the shattered membrane fragments fuse to generate the EOMV. OIMVs are comprised of two lipid bilayers, the outer membrane and inner membrane from the parent bacteria as well as the membrane proteins, while the EOMV only has one lipid bilayer from the original outer membrane. Both EOMV and OIMV contain cytosolic cargo (e.g. small-molecule metabolites, genomic DNA, RNA, endolysin, virulence component, etc.) that differ from the OMVs [29].

Besides, in the specific Gram-positive bacteria, endolysin will initiate the bubbling cell death by hydrolysis of the thick peptidoglycan cell wall, potentiating the formation of cytoplasmic membrane vesicles (CMVs) [7]. CMVs formation is attributed to the stress-mediated bacteria lysis, peptidoglycan degradation by exogenous endolysins, and drug-induced suppression of cell wall biosynthesis. CMVs also contain the cytosolic cargo from Gram-positive bacteria, similar to the EOMVs and OIMVs [30]. Notably, the different composition and structure of BEVs resulted in distinct biological functions in the physiological environment, especially for their interaction with the host immune system [31]. Hence, the BEVs attracted great interest from academia and industries to be utilized as nanopharmaceuticals for biomedical applications, especially for drug delivery and vaccination to combat various diseases.

3 Internalisation of BEVs into host cells

As key messengers for microbiota-host communications, BEVs carry a wide range of cargoes such as proteins, DNA, and RNA. The majority of these “messages” are compartmentalized inside BEVs and are required to be released into the host cells to facilitate cellular events [32, 33]. For this to happen, BEVs need to enter host cells and ultimately release these cargoes untainted for them to fulfill their biological roles. Depending on their origination, the exterior of BEVs is decorated with ligands such as LPS, lipoproteins, and other virulent factors [34]. These ligands play an important role in the internalization of BEVs, as their interaction with different receptors on the host cell triggers different internalization pathways [35]. The internalization pathway taken by BEVs is also influenced by the size of BEVs [36], the type of host cells along with many other unknown factors [37]. The internalization processes of BEVs by host cells remain underexplored, but a few major pathways have been proposed and studied (Fig. 3).

The most common internalization pathway utilized by extracellular entities such as BEVs is phagocytosis, particularly for entry into phagocytotic immune cells such as neutrophils, dendritic cells, and macrophages [38]. Notable examples of BEVs internalized via phagocytosis are Streptococcus pneumoniae [38] and Mycobacterium tuberculosis [39, 40]. Phagocytosis is initiated by phagocytic receptors, which trigger a signaling cascade leading to the rearrangement of lipid membranes and the actin cytoskeleton [40]. Phagocytosis is initiated by phagocytic receptors, which triggers a signaling cascade leading to the rearrangement of lipid membranes and the actin cytoskeleton, ultimately resulting in the surrounding of the BEVs [41], eventually forming phagolysosomes in which the BEVs may be degraded to release their internal cargo [42].

BEVs are also found to enter non-phagocytotic cells such as epithelial cells, suggesting that many other non-phagocytotic pathways are possible [35]. An example of such pathways is Clathrin-mediated endocytosis (CME) [43, 44]. The initiating ligands and relevant receptors are poorly understood, but the formation of clathrin-coated pits has been well studied. The first proteins that assemble at the site of BEV docking are clathrin, which is followed by an assortment of structural proteins to form a clathrin-coated pit. Dynamin2 is further recruited at the neck of the develo** invagination, which undergoes GTP hydrolysis-dependent conformational changes to cut off the nascent intracellular vesicle [45]. The BEV-carrying intracellular vesicles fuse with endosomes and eventually release their cargoes upon disintegration of the BEV lipid bilayer. This pathway is exclusively taken by BEVs of Lactiplantibacillus plantarum [46], where the uptake of the BEV was blocked upon treatment with CME inhibitor chlorpromazine. However, the internalization of BEVs may not rely solely on one pathway; instead, multiple pathways can be simultaneously utilized. As in the case of Borderella bronchiseptica [43], their internalization into AW264.7 cells was decreased upon the inhibition of either micropinocytosis with cytochalasin D and CME, suggesting that the BEVs rely on both micropinocytosis and CME for internalization.

BEVs along with pathogens such as viruses and bacteria, can invade host cells through receptor triggered-internalization pathways such as Caveolin-mediated endocytosis [47]. This is a preferred pathway as the resulting intracellular caveolae are believed to not fuse with lysosomes [48, 49] hence ensuring the survival of the invading pathogens. Caveolin-mediated endocytosis is initiated with the binding of ligands and virulent factors like folic acids [50], alkaline phosphatase [51], cholera toxin [51], and viruses like HIV1 [52]. This is followed by oligomerization of caveolin proteins on lipid raft domains to form the flask-shaped invaginated caveolae [53]. The caveolae pinch in a GTP-dependent manner similar to Clathrin-coated pits to form caveosomes, whose intracellular fate depends on their content [49]. Caveosomes containing the SV40 virus were found to have neutral pH and do not fuse with lysosomes [54], while albumin-rich caveosomes were trafficked along the endosomal degradation pathway [55]. It can be inferred that the interactions between cargo and caveolar components play a role in the destination of caveosomes [49]. In the works of Franz G. Zingl, outer membrane protein (Omp) OmpU and OmpT were found to be essential for the predominant caveola-mediated internalization of V. cholerae BEVs [56]. These BEVs protected the virulent factor cholera toxin (CT) from extracellular trypsin and successfully releasing them in HT29 cells. This reiterates the importance of surface ligands in the initiation of Caveolin-mediated endocytosis which allows successful delivery of cargoes into host cells.

The endocytosis pathways mentioned earlier involve the coating of the entire BEV including its lipid bilayer, with transmembrane proteins like Caveolin to form intracellular vesicles. However, there are also pathways taken by BEVs in which only the internal cargo is internalized without the lipid bilayer of the BEV. One such pathway is Membrane fusion, which is a process triggered by the binding N-ethylmaleimide-sensitive factor (NSF)-attachment protein receptors (SNAREs) [57]. This pathway requires the presence of Ca²⁺ ions and it is observed that during fusion, the phospholipid bilayers of BEVs adhere and assimilate with host cell [57]. This is well demonstrated by Bomberger et al., where the fluorescence of Rhodamine‐R18 membrane-labelled P. aeruginosa BEVs were increased when treated to mammalian epithelial cells, showing a mixing of lipids between the two bilayers and eventual dilution of the previously quenched dye [58].

Another internalization pathway taken by BEVs is through Toll-like receptors (TLR), a family of cellular receptors that recognizes microbial molecules [92]. BEVs of Neisseria meningitidis were reported to stimulate B cells to produce cross-reactive antibodies that were bactericidal towards both Neisseria meningitidis and Neisseria gonorrhoeae [93]. This was possible as the 2 pathogens display similar antigens (PorA/B and lipooligosaccharide) on the whole cell and their BEVs. Meanwhile, the BEVs of Neisseria lactamica OMVs could induce tonsillar B cells to produce polyclonal IgM and increase the proliferation of a subset of B cells, through a mechanism that is possible via a mitogenic ligand and B cell receptor interaction [94]. Mice injected with BEVs of Salmonella typhimurium displayed high amounts of antigen-specific IgG produced by B cells and were protected against live Salmonella typhimurium challenge 14 days after injection, suggesting an established adaptive immunity [89]. Studies on Neisseria meningitidis BEV-based vaccines show that memory B cells were activated and isolated upon vaccination [95, 96].

The interactions between BEVs and various components of the immunity systems to elicit innate and adaptive responses entail the potential of using BEVs as vaccines to induce immunity against future infections. It is potentially safer to utilize BEVs as vaccines as compared to attenuated cells or whole cells as BEVs themselves are not propagative and thus will not lead to serious infections/adverse reactions, as opposed to when using live bacteria [97].

5 Recent advances in BEVs-based nanopharmaceuticals

5.1 BEVs as drug delivery platform

5.1.1 BEV delivery of gene therapy

In recent years, a new form of pharmacological approach to treating disease is Gene therapy. Gene therapy involves the introduction of genetic materials such as DNA or RNAs and enzymes like nucleases or genome editing enzymes [98]. These materials are introduced into host cells often for gene silencing (using miRNA, siRNA, and shRNA), gene introduction via plasmids, naked genetic materials, and gene editing using nucleases or clustered regulatory interspaced short tandem repeats (CRISPR)/CRISPR-associated protein (Cas)-associated nucleases [99]. Gene therapy has emerged as a potent treatment modality, with several genetic-based treatments demonstrating clinical success [100]. Unfortunately, genetic materials and their associated enzymes are highly susceptible to degradation both ex vivo and in vivo, rendering them suitable for direct introduction into hosts [114]. Recent development have utilized pre-miRNA instead, which are shorter precursors of miRNA that can be processed into mature miRNA for RNA interferences [115]. However, these approaches are still plagued by synthetic difficulties, degradation by intracellular nucleases, and poor loading into nanocarriers which are often toxic [116]. Inspired by these challenges, Cui et al. developed a msbB mutated E. Coli BL21 derived BEVs carrying tRNA^Lys-pre-miR-126 (Fig. 5C) [117]. The unique cargo is a pre-miRNA that is disguised with a “tRNA scaffold”, which is more stable and can be amplified into mature miRNAs in host cells [118]. The highly biocompatible BEVs targeted tumor cells in mice specifically with the AS1411 aptamer on their surfaces and lowered the expression of CXCR4, effectively lowering tumor proliferation. This study shows that BEVs can be bioengineered to be superior and safe nanocarriers that can accommodate non-conventional genetic cargoes.

In addition to delivering various forms of RNAs for gene therapy, BEVs can also serve as carriers for DNA, acting as adjuvants for vaccines. In the works of Qiong Liu et al., DNA was delivered in the form of eukaryotic expression plasmid coding for cytokines IL17A or INF-γ in H. pylori BEVs (Fig. 5D) [119]. The recombinant BEVs were used in conjunction with UreB and whole inactivated cells as the vaccine antigen. Mice injected with the BEV adjuvants had higher levels of anti-H. pylori IgG antibodies and a more lasting expression of IL-17A and IFN-γ than control groups. When challenged with H. pylori infection, mice immunized with the recombinant BEVs adjuvants showed lower H. pylori colonization than wild-type H. pylori and Chlorea Toxin as adjuvants. Overall, the recombinant BEVs were able to induce stronger humoral, and mucosal immune responses and protected hosts from H. pylori infections. This study serves as an example demonstrating that BEVs can effectively deliver DNA cargo, acting as adjuvants for vaccine development.

In addition to gene silencing or gene introduction, gene editing through Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 has proven to be a powerful method for permanently knocking out genes [121]. However, guide RNAs and CRISPR-Cas 9 enzymes used in CRISPR-Cas-9 gene therapy are susceptible to degradation by nucleases and their poor penetration and selectivity into target cells have limited their application as a viable treatment modality [122, 123]. To fully draw upon the prowess of CRISPR-Cas 9 gene editing, Min Li et al. developed a novel bacterial nanomedicine (BNM) based on polymer-lipid hybrid nanoparticles and BEVs from attenuated Salmonella to deliver CRISPR-Cas 9 to Dendritic Cells [120] (Fig. 5E). The BEV-derived LPS conferred Dendritic Cell (DC) targeting capabilities to the Biomimetic Nanoparticles (BNMs) through TLR4-PAMPs interactions. BNMs with higher BEV to NP ratios exhibited increased uptake by DCs, consequently leading to elevated expression of costimulatory molecules CD80, CD86, and CD40 in these DCs. The CRISPR-Cas9 system delivered by these BNMs successfully knocked out the YTHDF1 gene in DCs, leading to CD8 + T cell-mediated tumor inhibition in MC38 tumor-bearing mouse models. The targeted delivery of sensitive RNAs and CRISPR-Cas9 specifically to dendritic cells (DCs) for DC activation and tumor inhibition underscores the significant potential of BEVs as a versatile delivery platform for effective gene therapies.

5.1.2 Therapeutic molecular cargo

The use of small molecules and biologics for the treatment of diseases has always been the mainstream modality since the dawn of modern medicine [124]. Despite their extensive use as therapeutics against diseases, they also suffer limitations as well, such as non-selectivity leading to adverse side effects and susceptibility to metabolism in vivo [125, 126]. As mediators between bacterial interspecies communication or bacteria–host interkingdom interaction, BEVs have intrinsic targeting capabilities that can bring chemical/biological messengers to the intended destination [127]. These properties can be hijacked by loading small molecules or biological drugs into specially engineered BEVs, in which they can be delivered specifically to the site of infection/disease. This results in the accumulation of therapeutic molecules at the target site, enhancing the therapeutic effect and reducing adverse effects due to off-target interactions [124]. Moreover, the loading of drugs into BEVs protects them from metabolism or degradation during their circulation to the target site. Consequently, this enhances the effective drug concentration at the target site and mitigates toxicity issues associated with drug metabolism [128]. Thus, there have been many advances utilizing BEV-based drug delivery platforms to overcome the limitations of small molecule and biological drugs [124, 129].

The small size and interactive nature of host cells [130] of BEVs enable them to cross multiple membranes and physical barriers in the human body. An example of a membrane barrier is the blood–brain barrier (BBB), which divides the brain from the peripheral circulation, maintaining homeostasis and the brain microenvironment [131]. Its highly lipophilic nature prevents 98% of drugs from reaching the brain and exerting their intended therapeutic effects [132]. Neutrophils were reported to be able to pass through the BBB and their expression of TLRs facilitates the interaction and uptake of BEVs [133]. Based on these desirable properties of neutrophils, Pan et al. loaded pioglitazone E. Coli BEVs with (OMV@PGZ), which would hitchhike onto neutrophils to cross the blood–brain barrier to enhance Ischemic Stroke Therapy (Fig. 6A) [134]. Neutrophils can engulf OMV@PGZ within 90 min, effectively cross the BBB, and release the intracellular OMV@PGZ after arriving at the ischemic area, where excess reactive oxygen species (ROS) induces the disintegration of neutrophils to form neutrophil extracellular traps (NETs). The release of PGZ in ischemic sites activates peroxisome proliferator-activated receptor (PPARγ), which ultimately exerts neuroprotective effect in transient middle cerebral artery occlusion (tMCAO) mice models. In this study, the unique immunogenicity between BEVs and neutrophils was taken advantage of to deliver small molecular drugs across the BBB.

BEVs have unique targeting abilities that can be utilized to load and deliver therapeutic drugs to disease sites. Chemotherapy drugs such as Doxorubicin are used as frontline drugs in the treatment of various cancers [135]. However, the non-selective nature of Doxorubicin (DOX) has resulted in severe adverse effects such as myelosuppression and immunosuppression, greatly reducing their application in the clinical setting [136, 137]. Previous studies have attempted to address selectivity issues by loading DOX into liposomes. However, these liposomal themselves are plagued with toxicity issues as well [138]. BEVs are superior alternatives to liposomes as they are highly biocompatible, and their outstanding immunogenicity may induce a local immune response which may augment the anti-tumor effects of DOX [139]. This is exemplified in the works of Kuerban et al., who loaded DOX into attenuated Klebsiella pneumonia BEVs (DOX-OMV) as a treatment for non-small-cell lung cancer (NSCLC) (Fig. 6B) [140]. Compared to free DOX, DOX-OMVs displayed superior pharmacokinetic properties, higher uptake, and a more potent cytotoxic effect in A549 cells. Interestingly, the empty BEV carrier exhibited a more potent antitumor effect than free DOX and DOX-liposomes, which was suggested to be contributed by the BEV-induced accumulation of macrophages at the tumor site. In another example, Zhuang et al. constructed the E. Coli-derived OMVs by encapsulating the inhibitors (UNC2025) of myeloid-epithelial-reproductive tyrosine kinase (MerTK) to block the efferocytosis of apoptotic tumor cells [9A) [198]. The spike proteins are characteristic of SARS-CoV-2 and are involved in the pathogenicity of the virus [199], qualifying them as ideal antigens for vaccine development. The spike proteins were initially recombinantly expressed on mammalian cells to preserve their native three-dimensional structure [200], while BEV components serve as adjuvant to boost the immune response. The HMVs were quickly internalized by DCs and increased MHC expression. Mice immunized with HMV exhibited a biased Th2-mediated humoral response and induced active T cell response with an increased expression of IFN-g and IL-6. This suggests that HMVs could serve as potential candidates for a BEV-based vaccine against SARS-CoV-2. Successful vaccines are intended for intramuscular administration and inducing systemic immunity. However, intranasal vaccines can induce local mucosal immunity and prevent further transmission of diseases [201]. Consequently, an intranasal vaccination strategy based on Neisseria meningitidis BEVs carrying D614G spike protein (mC-Spike) of SARS-CoV-2 was developed [201]. The nanovaccine (OMV-mC-Spike) was composed of LPS-bound HexaPro Spike-mCRAMP conjugate, in which mCRAMP contributed to binding to LPS on the BEV surface while HexaPro Spike [202] served as a previously optimized antigen of SARS-CoV-2. Intranasal administration of OMV-mC-Spike to mice induced higher levels of IgG and IgA titers in serum, nasal washes, and lungs. Hamster models subjected to the viral challenge after immunizing with OMV-mC-Spike displayed the lowest viral loads and reduced lower respiratory tract diseases afterward. The versatility of BEVs to accommodate different cargoes and antigens allows the rapid development of BEV-based vaccines against novel diseases.

The influenza virus is an RNA-based virus, and its frequent mutations lead to changes in antigenicity, complicating the development of a cross-subtype vaccine [202, 203]. Doo-** Kim’s group has previously developed BEV-based vaccines using E. Coli BEVs, wherein the LPS is modified with a lipid A 40-phosphatase (fmOMV) [204]. The adaptive immune response triggered by fmOMV was investigated recently (Fig. 9B) [205]. Mice injected with fmOMVs exhibited high levels of HA-specific antibodies, as well as HA- and NP-specific IgA and IgG antibodies, which suggest a cross-immunity against influenza mutants. When challenged with several strains of influenza, fmOMV immunized mice displayed pronounced IFN- γ -producing T cells and were protected against all tested strains 18 weeks post-vaccination. This study demonstrates the immunogenicity of modified BEVs alone, without viral antigen can be utilized as vaccines against influenza.

Human-immunodeficiency virus (HIV), Human Papilloma Virus (HPV), and Hepatitis C (HCV) are sexually transmitted viruses that cause diseases such as AIDS, Cervical Cancer, and Liver Cancer [206]. These diseases are chronic or lifelong, posing a significant global health challenge that requires urgent attention and solutions [207]. Furthermore, there are currently only medications available to manage the symptoms of these diseases, with no cure currently available [208]. Vaccination is the only effective method to prevent the spread of these diseases but so far, only approved vaccinations against HPV are available [208, 209]. As highly immunogenic carriers and versatile platforms for the expression of foreign proteins, BEVs may be used for the development of antiviral vaccines as they can act as adjuvants or express viral antigens via recombinant technology. Earlier attempts at develo** BEV-based vaccines against these viruses and diseases have been made [210, 211].

The quest for an effective HIV vaccine has been an arduous journey spanning over 40 years [212]. Prototypes developed thus far often suffered from adverse effects and exhibited weak targeting capabilities [213]. A recent endeavor to develop a BEV-based HIV vaccine involved incorporating the HIV-1 envelope membrane-proximal external region (MPER) into the outer membrane protein OmpF as a construct in E. Coli Nissle 1917 and their BEVs (Fig. 9C) [214]. The MPER-OmpF decorated BEVs were antigenic to MPER-binding HIV-1 gp41 (2F5) monoclonal antibody, suggesting its potential as a viable vaccine candidate awaiting further studies.

Human papilloma viruses (HPV) are non-enveloped viruses consisting of more than 200 subtypes, 15 high-risk subtypes known to cause Cervical Cancer [215]. Current clinically applied HPV vaccines are based on virus-like particles composed of the L1 protein. However, they are limited by their type restriction, instability, and high production costs [216]. Prior studies using HPV L2 proteins provided wide strain protection as the L2 protein sequence contains a major cross-neutralization epitope and induced broadly neutralizing anti-HPV antibodies [216, 217]. A recent advance in HPV vaccine development involved the construction of a BEV-based vaccine displaying an L2 protein polytope that is made up of amino acid sequences from 8 HPV serotypes (Fig. 9D) [216]. The E. Coli BL21(DE3)∆60 BEV-based vaccine induced L2-Specific IgG Titers in immunized mice and neutralizing titers in in vitro pseudovirus neutralization assay. A laboratory-scale production process was also conducted to demonstrate the scalability of the production of this BEV-based vaccine. The limitation of current HPV vaccines is that they only protect against HPV naïve individuals and provide no therapeutic value to HPV-positive or patients with cervical cancer. A tentative therapeutic vaccine was prototyped by Chen et al., in which the HPV-associated peptide E7 was recombinantly expressed in E. Coli BEVs to form a nanovaccine (Fig. 9E) [216]. E7p-OMV protected the internally loaded E7 peptides from proteases and when injected into mice, displayed tumor suppressive effects. This was found to be mediated by increased antigen expression in DCs, specific Th1 (CD4 + IFN-γ +) responses, and CTL (CD8 + IFN-γ +) responses. This study has the potential to pave the way for future developments in therapies for HPV-associated cancers, which are currently lacking and in high demand.

Cirrhosis and hepatocellular carcinoma are caused by Hepatitis C (HCV), and currently, there are no clinically licensed vaccines available for prevention against HCV infections [218]. Prior attempts to develop an HCV vaccine involved the truncation of protein NS3 but were faced with a weak invocation of the immune response [219]. An adjuvant may be required to boost the immune responses of such vaccines. A recent study developed a Neisseria meningitidis serogroup B BEV-based vaccine platform with recombinant truncated core1-118 (rCore) and NS31095-1384 (rNS3) fusion protein (rC/N) against HCV (Fig. 9F) [220]. The rC/N-BEV vaccine induced higher IgG1 and IgG2a levels, indicating a Th1/cellular response and outperforms combinations of rC/N with other adjuvants. This study demonstrates the superior adjuvant properties of BEVs and their potential as a platform for the development of future HCV vaccines.

5.2.3 Cancer

Notably in recent decades, the development of vaccines has been recognized as a new weapon to combat tumors and potentiate the expansion of oncologic armamentarium [221]. Among the emerging nanovaccines and pharmaceuticals, bacteria and their derived extracellular vesicles attract great interest to be applied as the new generation of cancer vaccines to achieve efficient immunotherapy [26, 222, 223]. Particularly, bacteria localized in the tumor microenvironment could build up the precise interaction between cancer cells, tumor-infiltrating immune cells, and other overexpressed biomarkers (e.g. cytokines, chemokines), remodeling the immune-suppressed microenvironment in the tumor site. The abundance of pathogen-associated molecular patterns in the bacteria demonstrates the desirable immunogenicity to activate the systemic immune response [224]. However, injection of intact bacteria containing intracellular contents (e.g., endotoxins, genetic material, etc.) into the patients always leads to severe safety concerns and potential side effects, thus the improvement of bacterial-inspired vaccines is highly demanded [225, 226]. The bacterial extracellular vesicles, especially outer membrane vesicles (OMV), show great promise to maintain the immunogenicity for in situ immune activation with considerable biosafety compared with weakened bacteria. Moreover, the small size of OMV (20–250 nm) also benefits the lymphatic drainage and long-term accumulation of antigens by enhanced permeability and retention (EPR) effect, thus improving the immunotherapy specificity [227, 228]. Particularly, Kim et al. first reported that using E. Coli OMV as cancer immunotherapeutics, which could efficiently localize in tumors due to their nano-size, inducing the production of interferon-γ and CXCL10 cytokines for tumor regression [227]. Besides, thanks to the hollow structure of OMVs for encapsulating the immunoadjuvant or antigens payload into the BEVs, the bacterial-derived nanopharmaceuticals could further reshape the suppressed immune environment in situ as antigen sources and boost the therapeutic efficiency, potentiating their great promise as a novel nanoplatform for the cancer vaccine’s development.

Benefiting from the advanced gene engineering technologies and molecular biological methods (e.g. DNA transfection, CRISPR-cas9, Gene sequencing) [229], diverse engineered bacteria have been developed to originally produce the antigens or cytotoxic protein compounds, flexibly modify the payload in the extracted BEVs or functionalize the nanopharmaceuticals for versatile tumor vaccination. For instance, to directly deliver the therapeutic cargo to the tumor site, Chiang et al. have genetically tailored probiotics E. Coli Nissle 1917 to secret the therapeutic OMVs loaded with small cytotoxic protein (HlyE) [230]. Oral administration of engineered bacteria illustrated effective tumor colonization. In response to the arabinose metabolism, HlyE-loaded OMVs contained personalized antigens to boost the dendric cell uptake, suggesting the significant tumor regression in the xenograft colorectal tumor model.

Moreover, genetic modification of bacteria could be leveraged to fuse the functional protein onto the cytolysin A (ClyA), which naturally existed on the membrane of BEVs, thus directly expressing antigens on the vesicle’s surface. The fused protein (e.g. enzyme, antibody, RNA-binding proteins, fluorescent protein, etc.) on the membrane could also endow the diverse function to enhance the therapeutic performance of BEVs-based cancer vaccines. Particularly, Cheng et al. have developed a versatile OMV-based vaccine platform by fusing the diverse protein catchers onto ClyA, which allows the OMV vaccine to present multiple and distinct tumor antigens on the surface (Fig. 10A) [231]. Using genetic engineering, the flexible OMV vaccine could fuse the target antigens onto the ClyA and activate the T cell for in situ antitumoral immune response. Importantly, the OMV vaccine has applied a Plug-and-Display system comprising diverse tag & catcher protein pairs, including the SpyTag (SpT)/SpyCatcher (SpC) pair and the SnoopTag (SnT)/SnoopCatcher (SnC) pair by fusing to the ClyA. By employing Plug-and-Display fused protein, different antigens could rapidly and simultaneously bind to OMV, realizing synergistic antitumor immunity, while the nanovaccine could efficiently abrogate lung melanoma metastasis and suppress colorectal tumor growth. Similarly, Li et al. have improved the “Plug-and-Display” strategy to deliver the mRNA antigens as the vaccine for antitumor immunotherapy (Fig. 10B) [232]. The RNA-binding protein, L7Ae, was fused onto ClyA and matched the binding sequence, box C/D was inserted into mRNA cargo for efficient loading of antigen on the OMV surface. Besides, the lysosomal escape protein, listeriolysin O was also fused with ClyA to improve the mRNA delivery efficiency in the dendritic cells (DCs), while the fused protein endowing the escape of nanovaccine from lysosome and cargo accumulation in the cytoplasm. The OMV-based mRNA vaccine could activate the innate immunity and subsequent cross-presentation in DCs, suggesting the efficient regression of melanoma and MC38 colon cancer model (Fig. 10C). Moreover, the genetic fusion on ClyA could also present the targeting ligand to improve the precise tumor targeting of OMV-based vaccines. Adriani et al. have genetically engineered the high-affinity anti-EGFR ligand, the single-chain variable fragments originated from panitumumab antibody, on the ClyA protein to construct the bioengineered OMVs for specific tumor accumulation, potentiating the application of these immunotherapy agents in different types of tumors [233].

To further improve the antitumor specificity of BEV-based vaccines, antigen-expressed cancer cell membrane particles, and extracellular vesicles have been employed to fuse with bacteria-derived vaccines to form hybridized nanopharmaceuticals [234]. Typically, the pure cytoplasmic membrane extracted from bacteria reserved abundant PAMPs to mobilize the immune system. L Chen et al. have hybridized the E. Coli cytoplasmic membrane and autologous tumor membrane to construct the fused membrane platform (HM-NPs), realizing the colocalization of antigens and adjuvants in the dendritic cell [235]. The bacterial cytoplasmic membrane was pretreated with lysozyme to remove the LPS and other cell wall components to prevent potential cytotoxicity. Such hybridized nanovaccine illustrates significant antitumor immune activation and diverse tumor ablation in colon, breast, and melanoma cancer mouse models. Benefiting from the fusion approach of BEVs and tumor EVs, recently, Tong et al. employed the outer membrane vesicle from Akkermansia muciniphila (Akk-OMV) as the self-immunoadjuvant to hybridize with antigen-rich tumor-derived exosomes for cancer vaccine construction (Fig. 10D) [236]. Besides, the Lipo@HEV formulation is supplemented with PD-L1 trap plasmid cargo to facilitate gene therapy for immune checkpoint inhibition, synergistically combating tumor growth by the hybridized OMV-based vaccine.

Different from conventional tumor vaccines inducing an adaptive immune response, recent advances in OMV-based vaccines try to improve immunogenicity by interfering with the immune-related signaling pathway. For instance, the long-term innate immune memory, known as trained immunity, which is referred to the procedure of modifying innate immune cells along with their hematopoietic progenitors to enhance nonspecific innate immunity [237, 238], particularly in reaction to subsequent infection or vaccination. The OMV-based vaccine could facilitate the trained immunity-related signaling pathway by the presence of PAMPs and other immunoadjuvants, which are independent of specific tumor-specific antigens. Particularly, Liang et al. have developed OMV-based nanohybrids by fusion of the recombinant protein of SIRPα and Fc fragment (SIRPα-Fc) on the surface to block the CD47-mediated immune escape (Fig. 10E) [239]. Following the subsequent calcium phosphate mineralization and loading of granulocyte–macrophage colony-stimulating factor (GM-CSF), the final OMV vaccine (OMV-SIRPα@CaP/GM-CSF) targets tumor-associated macrophages (TAMs) in the bone marrow to train the progenitor cells and monocytes for long term immunity. OMV-SIRPα@CaP/GM-CSF also illustrated efficient tumor regression by trained immunity in both MC38 tumor and B16-F10 tumor models with distinct T-cell-mediated immune responses, suggesting the different therapeutic mechanisms for vaccination formulation. Recent developments of BEV-based vaccination to enhance immunoreactivity were also considered to facilitate the cGAS-STING pathway in the dendritic cell to heighten the DC maturation. Zhang et al. constructed the interfacial nanocloak on the B. fragilis-derived extracellular vesicles by coating the biocompatible manganese oxide [240]. Once the nanocloaked BEVs internalized into the dendritic cell, the nanocloak layer will dissolve in the lysosome and release the Mn²⁺ to mobilize the cGAS-STING pathway for boosted maturation of DC, illustrating the amplified immunotherapeutic ability in breast cancer model.

6 Advantages of BEVs

Extracellular vesicles are key mediators of intercellular communication, shuttling biological and chemical messengers throughout the host. Extracellular Vesicles are produced by bacteria (BEVs) and mammalian cells as well, known as mammalian extracellular vesicles (MEVs). BEVs and MEVs have many similarities in common, such as their hollow nanostructure comprised of lipid bilayer membrane, stability in physiological environments, and their intrinsic targeting abilities attributed to their membrane proteome. These advantages have been exploited by researchers for the development of extracellular vesicle-based delivery platforms for biomedical applications. Notably, BEVs have several notable characteristics when compared to MEVs, suggesting BEV’s potential as promising nanopharmaceuticals, such as stability in the living system, penetrative capabilities, as well as ease of engineering and industrial production. One of the advantages of BEVs is their high yield and cost-effective production. As derivatives of bacteria, BEV production benefits from the advantages of industrial-scale bacteria cultivation. The short doubling time of bacteria allows for high cell density liquid cultures, which rely on cheap and readily available liquid medium, ensuring cost-effectivity [241]. Furthermore, hyper-vesiculating mutants of H. pylori and E coli have been developed to further increase the yields of BEVs [242, 243]. On the other hand, the production of MEVs often suffers from long culturing periods and low yields of exosomes [244]. Potentially, BEVs can serve as economical drug delivery agents with wide applicability across various therapeutic applications.

The lipid membranes of BEVs are also highly stable and resistant to a wide variety of enzymatic activities such as proteases and nucleases [245, 246]. This characteristic makes BEVs suitable vehicles for biomolecular-based cargoes that are sensitive to temperatures and enzymatic activities, such as proteins, enzymes, or genetic materials [245, 247,248,249]. By storing such sensitive biomolecules in BEVs, they can be delivered intact to their target site without degradation or loss of function, addressing a common issue that limits clinical implementation [250]. Additionally, BEVs can function as stabilizing “packages” allowing long-term storage of biomolecules at elevated temperatures. For example, when phosphotriesterase (PTE) was packaged into E. Coli BEVs survived storage at 37 °C for 14 days and multiple freeze–thaw cycles, preserving higher enzymatic activity compared to free PTE [245]. This ability suggests that heat-sensitive cargoes can be transported in BEVs without the need for expensive logistical processes (such as cryostorage) for extended periods [251], unlike SARS-COV -mRNA vaccines encapsulated in liposomes [252]. The effects of storage temperature on the quality of MEVs and their interior cargo remains inconclusive. Generally, MEVs may be less robust and unstable than BEVs, as the storage of MEVs requires specialized buffers and storage temperature of 4–20 °C for optimal activity [253, 254]. The remarkable ability of BEVs to stabilize and protect cargoes from physiological and physical environments makes them ideal carriers for drug delivery.

BEVs are excellent nanocarriers, as they have been reported to be able to penetrate the biological tissue barrier, such as the epithelial cell layer [252], target skeletal structures [110], and even bypass the blood–brain barrier (BBB) [255, 256]. This outstanding capability of BBB penetration addresses a major limitation in the progression of many promising neurological drug candidates targeting the Central Nervous System [257]. Notably, BEVs also exhibit outstanding targeting capabilities which are attributed to their membrane composition and intrinsic protein expression. The similarities in the membrane composition allow BEVs to have the affinity to parental bacteria whole cells while certain antigens can allow them to target bacteria from other species or strains [8, 258, 259]. Synergizing with their penetrative ability across tissue and cellular barriers, BEVs can realize precise biomedical strategies for bacterial infections. Furthermore, BEVs play a key role in the interaction between the host system and bacteria, by internalizing into mammalian cells through various pathways such as endocytosis, membrane fusion, and receptor-mediated signaling [35], potentiating the immune system activation for therapy. However, due to the difference in origin and membrane composition, MEVs lack bacterial cell targeting capabilities and are limited to only host or mammalian cells, restricting their strategic application in bacterial-induced diseases. Therefore, benefiting from their unobstructed bypass through various barriers, affinity to homotypic bacterial cells, and mediating the interaction between host cells and bacteria, BEVs can be employed as carriers to potentially revive previously unsuccessful therapeutics plagued with distribution, permeation, and stability issues in vivo [260].

Notably, owing to the mature genetic manipulation of bacteria, the expression of surface proteins, and functional sites on their membrane, the exterior of BEVs can be easily engineered for cargo loading or the regulation of their interactions with target cells [261, 262]. BEVs can be modified by cultivation in modified mediums, or even hybridization with other forms of nanoparticles and nanovesicles as exemplified in this review. This allows the development of facile BEV-based nanopharmaceuticals with diverse biomedical applications. Furthermore, isolated BEVs can also be further decorated with functional ligands via protein–ligand interactions [263], protein–protein interaction [264], or potentially bioconjugate reactions. Overall, these engineering strategies result in BEVs which are highly precise delivery platforms with improved therapeutic efficiencies to combat extensive biomedical challenges. As MEVs also originate from cells and have a similar membrane structure as BEVs, they can be similarly modified as BEVS, but the genetic modification of mammalian cells is generally more difficult as compared to bacteria, greatly limiting their scope of application.

Importantly, the advantage of BEVs is their immunogenic properties and ability to engage with the immune system. Other than simply serving as nanocarriers for drug delivery, BEVs can also serve as functional nanoagents that can stimulate immune responses which may augment the therapeutic effects of their cargo [140]. Furthermore, the immunogenicity of BEVs allows them to be utilized as vaccines to stimulate long-term immune response or act as adjuvants in combinational vaccines against cancers, and bacterial and viral infections [129, 265]. MEVs which are derived from mammalian cells have limited immunogenicity and lack exogenous antigen expression, impeding their immune response for therapy. MEVs have also been capitalized to develop vaccine platforms, but they have a narrower scope when compared to BEVs as they are mainly focused on antitumoral applications [266]. The unique immunogenicity of BEVs qualifies them to be a competitive platform for the development of functional nanopharmaceuticals.

7 Conclusion and further perspective

In this review, we comprehensively summarize the development of BEV-based nanopharmaceuticals to facilitate disparate biomedical applications in recent years. Amongst the unique advantages and functions of BEVs, we demonstrated the tremendous potential of applying these naturally occurring nanovesicles to establish a myriad of innovative therapeutic strategies for new-generation pharmaceuticals evolution, especially in the versatile bioactive cargo delivery and powerful vaccination approaches.

Taking the unique merits of nanovesicles, the structural stability, ease of cargo loading, promising penetration across physiological barriers, and specific targeting capabilities endow the BEVs application to be beneficial in delivery for a wide range of therapeutics. Particularly, the naturally occurring membrane structure of BEVs enables targeting delivery of therapeutic genetic tools (e.g., siRNA, DNA, CRISPR-Cas9, etc.) in the physiological, preserving stability and bioactivity, thus enhancing gene therapy. Leveraging the ease of genetic modification in parent bacteria, protein cargo, such as enzymes and antigens, can also be directly expressed within BEVs, optimizing loading efficiency compared to conventional delivery platforms. Furthermore, advancements in nanotechnology and material science have witnessed the integration of functional materials with BEV delivery platforms to achieve combinational therapy, thereby further improving the synergistic therapeutic efficacy.

However, several considerations regarding the optimization of BEV-based delivery platforms are still necessary to be taken care to propel the BEV nanopharmaceuticals into clinical translation. The current isolation of BEVs relies heavily on ultracentrifugation, which raises the concern of a time-consuming and energy-intensive nature [21]. The established technique cannot fully separate the BEVs from the lysis of parent bacteria, resulting in low purity of nanovesicles and making BEVs identification challenging [267]. Several affinity-based purification techniques (e.g. magnetic bead-mediated adsorption, antibody-based selection, etc.) [268, 269] resulting in high yield and purity of mammalian extracellular vesicles have been proposed and can be potentially translated for BEV isolation to increase their yield and achieve higher purities. Besides, the larger-scale production of BEVs from living bacteria may lead to inconsistencies in size and overall composition from batch to batch. Enhancements in standard harvesting procedures for BEVs and the culturing of parent bacteria are imperative.

Notably, by thanking the abundant display of native PAMPs and immunostimulatory antigens, BEVs exhibit unique immunogenicity making them promising vaccine platforms, while the self-adjuvating properties of BEVs stimulate host immune responses. BEV-based nanovaccines have demonstrated efficacy in preventing bacterial and viral infections, as well as combating tumors, highlighting their potential in addressing a wide range of diseases. Despite numerous promising achievements, the clinical practice of the BEV-based vaccination method remains controversial. It's crucial to recognize that PAMPs play a significant and intrinsic role in the pathogenicity of bacteria. Thus, the balance between biosafety and immunostimulatory of BEVs-based vaccines should be carefully considered. The inadvertent introduction of virulent factors (e.g. LPS and virulent protein) in extracted BEVs can lead to excessive immune stimulation, inflammatory responses, reactogenicity, or other adverse effects [259, 270, 271]. Moving forward, it is imperative to elucidate the pathogenicity of harmful components inherited by BEVs. Further investigation is necessary to develop improved methods for isolating and purifying BEVs, ensuring the removal of detrimental bacterial components that may pose a threat to the host before implementation, thereby minimizing adverse effects [272, 273]. This is especially critical when administering BEVs to immunocompromised individuals [274].

In conclusion, we believe that bacterial extracellular vesicles have emerged as a new era of innovative nanopharmaceuticals attributed to their outstanding advantages and attractive functions. Continued studies will undoubtedly explore the vast potential of BEVs as an indispensable and influential tool to boost biomedical applications, paving the way for their clinical translation and revolution of nanomedicine.

Availability of data and materials

The review is based on the published data and sources of data upon which conclusions have been drawn can be found in the reference list.

Abbreviations

BEV:: Bacterial extracellular vesicle
LPS:: Lipopolysaccharide
CME:: Clathrin-mediated endocytosis
TLR:: Toll-like receptors
PAMP:: Pathogen-associated molecular patterns
PRR:: Pathogen recognition receptors
IL:: Interleukin
TNF:: Tumour necrosis factor
AMP:: Antimicrobial peptides
hBD:: Human-β-defensin
BBB:: Blood–brain barrier
Rif:: Rifampicin
OMP:: Outer membrane protein
Ig:: Immunoglobulin
NSCLC:: Non-small-cell lung cancer
DOX:: Doxorubicin
APEC:: Avian pathogenic Escherichia coli
CRISPR:: Clustered regulatory interspaced short tandem repeats
OIMV:: Outer-inner membrane vesicles
EOMV:: Explosive outer membrane vesicles
CMV:: Membrane vesicles
CT:: Cholera toxin
PDT:: Photodynamic
ICG:: Indocyanine green

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Acknowledgements

This work is supported by MOE Tier 1 RG4/22, RG6/20, RG69/21, MoE AcRF Tier 1 Theme RT7/22, A*Star SERC A1983c0028, A20E5c0090, awarded at Nanyang Technological University (NTU).

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Ming Yao Ho and Songhan Liu have contributed equally to this work.

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School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, S637371, Singapore
Ming Yao Ho, Songhan Liu & Bengang **ng

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Ming Yao Ho
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Songhan Liu
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Bengang **ng
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S. Liu and M. Y. Ho wrote the manuscript, S. Liu and B. **ng guided the manuscript preparation. B. **ng gave corrections to enhance the manuscript's quality. All authors read and approved the final manuscript.

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Ho, M.Y., Liu, S. & **ng, B. Bacteria extracellular vesicle as nanopharmaceuticals for versatile biomedical potential. Nano Convergence 11, 28 (2024). https://doi.org/10.1186/s40580-024-00434-5

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Received: 06 April 2024
Accepted: 20 June 2024
Published: 11 July 2024
DOI: https://doi.org/10.1186/s40580-024-00434-5

Bacteria extracellular vesicle as nanopharmaceuticals for versatile biomedical potential