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Extracellular vesicles (EVs) from various sources, including edible plants, milk, bacteria and mammalian cells, have emerged as a platform for miRNA and drug delivery that seem to induce the expected immune effects locally and in distant tissues after oral administration. Such a possibility greatly expands the clinical applicability of EVs. Much focuses are on the EVs from edible plants and bacteria. Growing evidence has suggested possible therapeutic applications for nanoparticles derived from edible plants, especially when administered orally to induce immunomodulation. And it was emphasized that the important immunomodulatory impact of microbiota may also be mediated by microbial EVs, formerly called outer membrane vesicles (OMVs).
- Plant-Derived EVs
- Bacterial EVs
- Oral Therapeutics
1. Introduction
Recently, extracellular vesicles (EVs) that may contain microRNA (miRNA) molecules together with freely circulating miRNAs have attracted research attention as promising candidates for various preventive and therapeutic interventions. Therefore, a growing number of studies have evaluated the therapeutic potential of EVs and miRNAs, the possible maneuvers to increase their effectiveness in vivo, and their biodistribution, pharmacokinetics and pharmacodynamics. In this regard, selection of the most efficient route of administration is a crucial step that determines further properties of EV- and miRNA-based therapeutics.
Postulated cross-species and cross-kingdom transmission of small non-coding RNAs, particularly miRNAs, via the oral route remains controversial. However, it has been speculated that lipids support the intestinal transmission of miRNAs. This opened up another research direction, namely studies on EV-based transfer and functionality after oral delivery. As discussed in recent review [1], EVs from various donor organisms have recently emerged as a platform for miRNA and drug delivery via the oral route and seem to induce expected immune effects locally and in distant tissues.
2. Plant-Derived EVs in Cross-Kingdom Delivery
Recently, growing evidence has suggested possible therapeutic applications for nanoparticles derived from edible plants, especially when administered orally to induce immunomodulation. However, their entry pathways and activities are still debated. Studies on the epithelial cell line have suggested that apple-derived nanoparticles may be internalized by these cells in the intestines. Additionally, other target cells for orally administered nanoparticles have been proposed, including intestinal macrophages, dendritic cells (DCs) and mesenchymal stem cells.
Orally delivered grapefruit-derived nanoparticles were shown to ameliorate colitis in mice after absorption by intestinal macrophages likely through both micropinocytosis and clathrin-dependent pathways. Similar alleviation of colitis was observed in mice with orally administered broccoli-derived nanoparticles that appear to target mesenteric lymph nodes and intestinal DCs. Other research described a protective effect against severe colitis in mice administered with nanoparticles derived from grapes that were found to be micropinocytosed by intestinal stem cells. This phenomenon may be of great importance in homeostasis maintenance because self-renewal of the intestinal epithelium is necessary to support proper integrity. Grape-derived nanoparticles were also found to be resistant to the artificially created environment of the stomach. This provides further evidence of the effectiveness of an approach based on the use of plant-derived EVs in remodeling intestinal cells and exploiting the therapeutic effects of this process.
Nanoparticles obtained from acerola juice appear to conjugate with miRNA molecules, which makes the latter more stable in RNase, acidic and alkaline environments when compared with miRNA conjugated with human breast milk EVs. Acerola nanoparticles seem to be taken up by intestinal macrophages and then distributed via circulation to different organs, predominantly to the intestine, liver and bladder. Interestingly, some were also detected in mouse brains, indicating the possibility of using this route of administration to deliver miRNAs to the central nervous system. Conversely, orally administered ginger-derived nanoparticles were primarily expressed in the liver and mesenteric lymph nodes but not in other organs in mice.
However, the role of plant-derived nanoparticles in cross-kingdom delivery remains controversial. Some studies failed to detect plant-enriched miRNAs in the plasma of different animals after plant product ingestion, while others demonstrated the presence of plant-derived miRNAs in mouse and human sera. Furthermore, some studies suggest the possibility of regulating mammalian cell transcripts by exogenous, diet-derived miRNAs. This leads to the idea of supplementing food with therapeutic miRNAs. However, currently, the scientific community is far from being convinced of this idea, especially as some studies indicate an insufficient passage of exogenous plant miRNA to mouse sera after oral feeding. On the other hand, miRNAs from edible plants may modulate gut microbiota, and such possible changes would in turn impact the body’s functioning. However, after absorption from the gastrointestinal tract, plant miRNAs may potentially target immune cells, and thus could play an important role in immune regulation. Accordingly, EVs appear to be the most efficient vehicles for the oral delivery of plant miRNAs. On the other hand, EVs are also considered to be interesting carriers for favorable food additives, improving the nutritional value of food to increase their stability and bioavailability.
3. Bacterial EVs
One of the most abundant species in human gut microbiota, Akkermansia muciniphila, acts as a “self-probiotic”, and its presence is inversely related to metabolic inflammatory disorders, including obesity and type 2 diabetes. Interestingly, both A. muciniphila and its EVs, administered orally reduced body weight in mice fed with a high-fat diet and normalized the permeability of the intestinal barrier through the regulation of tight junctions, and also affected serotonergic gene expression, both in the colon and hippocampus, indicating that bacterial EVs had an impact on the gut–brain axis. Furthermore, it has been suggested that the possible penetration of the brain by orally administered Paenalcaligenes hominis-derived EVs through the blood and the vagus nerve may promote cognitive impairment in mice. Metagenomic data revealed significant changes in stool EVs’ composition caused by inflammatory bowel disease (IBD), affecting A. muciniphila- and Bacteroides acidifaciens-derived EVs in particular. Moreover, oral application of A. muciniphila-derived EVs triggered a protective effect against IBD, which was manifested in a reduction in weight loss and colon inflammation. EVs derived from a probiotic strain of Escherichia coli Nissle 1917 ameliorated inflammation and clinical symptoms of colitis in mice. Similar effects were induced by Lactobacillus rhamnosus-derived EVs by regulating murine gut microbiota. It has been reported that Helicobacter pylori-derived EVs delivered intragastrically to mice may modulate both innate and adaptive immune responses.
Bacterial-derived EVs appear to be candidates for mucosal vaccines causing immune protection against specific pathogens. Accordingly, massive production of both intestinal sIgA as well as serum IgG antibodies against EV-transmitted antigens was noted in mice that were orally immunized with three doses of chitosan-coated Campylobacter jejuni-derived EVs together with the induction of a specific cell-mediated immune response. Furthermore, after a subsequent intragastric challenge with C. jejuni, a significant reduction in the bacterial load and only slight histological changes in the cecal tissue was observed in immunized animals. Similarly, four intragastric administrations of H. pylori-derived EVs with a cholera toxin as an adjuvant protected mice from H. pylori infection by activating the production of antibodies specific for EVs’ outer membrane protein. Another example of a mucosal vaccine is described in studies on EVs derived from Vibrio cholerae. Immunization with EVs caused a long-lasting increase in antibody titers in serum depending on the route of administration. Intragastric vesicle delivery caused particularly robust responses in IgG1 and IgG2. Interestingly, the offspring of orally immunized mice were also protected from infection with V. cholerae.
Altogether, plant-derived nanoparticles and bacterial EVs seem to play an important immunomodulatory role and could be considered promising candidates for the oral delivery of various therapeutics.
This entry is adapted from the peer-reviewed paper 10.3390/ijms23147554
References
- Martyna Cieślik; Katarzyna Nazimek; Krzysztof Bryniarski; Extracellular Vesicles—Oral Therapeutics of the Future. International Journal of Molecular Sciences 2022, 23, 7554, 10.3390/ijms23147554.
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