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Open AccessArticle

Plant-Derived Extracellular Vesicles as a Delivery Platform for RNA-Based Vaccine: Feasibility Study of an Oral and Intranasal SARS-CoV-2 Vaccine

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Margherita A. C. Pomatto

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Chiara Gai

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Federica Negro

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Lucia Massari

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Maria Chiara Deregibus

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Cristina Grange

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Francesco Giuseppe De Rosa

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Giovanni Camussi

Pharmaceutics 2023, 15(3), 974; https://doi.org/10.3390/pharmaceutics15030974 - 17 Mar 2023

Viewed by 518

Abstract

Plant-derived extracellular vesicles (EVs) may represent a platform for the delivery of RNA-based vaccines, exploiting their natural membrane envelope to protect and deliver nucleic acids. Here, EVs extracted from orange (Citrus sinensis) juice (oEVs) were investigated as carriers for oral and [...] Read more.

Plant-derived extracellular vesicles (EVs) may represent a platform for the delivery of RNA-based vaccines, exploiting their natural membrane envelope to protect and deliver nucleic acids. Here, EVs extracted from orange (Citrus sinensis) juice (oEVs) were investigated as carriers for oral and intranasal SARS-CoV-2 mRNA vaccine. oEVs were efficiently loaded with different mRNA molecules (coding N, subunit 1 and full S proteins) and the mRNA was protected from degrading stress (including RNase and simulated gastric fluid), delivered to target cells and translated into protein. APC cells stimulated with oEVs loaded with mRNAs induced T lymphocyte activation in vitro. The immunization of mice with oEVs loaded with S1 mRNA via different routes of administration including intramuscular, oral and intranasal stimulated a humoral immune response with production of specific IgM and IgG blocking antibodies and a T cell immune response, as suggested by IFN-γ production by spleen lymphocytes stimulated with S peptide. Oral and intranasal administration also triggered the production of specific IgA, the mucosal barrier in the adaptive immune response. In conclusion, plant-derived EVs represent a useful platform for mRNA-based vaccines administered not only parentally but also orally and intranasally. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessArticle

Doxorubicin Loading into Milk and Mesenchymal Stem Cells’ Extracellular Vesicles as Drug Delivery Vehicles

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Pharmaceutics 2023, 15(3), 718; https://doi.org/10.3390/pharmaceutics15030718 - 21 Feb 2023

Viewed by 445

Abstract

Extracellular vesicles (EVs) have great potential as drug delivery vehicles. While mesenchymal/stromal stem cell (MSC) conditioned medium (CM) and milk are potentially safe and scalable sources of EVs for this purpose, the suitability of MSC EVs and milk EVs as drug delivery vehicles [...] Read more.

Extracellular vesicles (EVs) have great potential as drug delivery vehicles. While mesenchymal/stromal stem cell (MSC) conditioned medium (CM) and milk are potentially safe and scalable sources of EVs for this purpose, the suitability of MSC EVs and milk EVs as drug delivery vehicles has never been compared and so was the objective of this study. Here EVs were separated from MSCs’ CM and from milk and were characterised by nanoparticle tracking analysis, transmission electron microscopy, total protein quantification, and immunoblotting. An anti-cancer chemotherapeutic drug, doxorubicin (Dox), was then loaded into the EVs by one of three methods: by passive loading or by active loading by either electroporation or sonication. Dox-loaded EVs were analysed by fluorescence spectrophotometer, high-performance liquid chromatography (HPLC), and imaging flow cytometer (IFCM). Our study showed that EVs were successfully separated from the milk and MSC CM, with significantly (p < 0.001) higher yields of milk EVs/mL starting material compared to MSC EVs/mL of starting material. Using a fixed amount of EVs for each comparison, electroporation achieved significantly more Dox loading when compared to passive loading (p < 0.01). Indeed, of 250 µg of Dox made available for loading, electroporation resulted in 90.1 ± 12 µg of Dox loading into MSC EVs and 68.0 ± 10 µg of Dox loading into milk EVs, as analysed by HPLC. Interestingly, compared to the passive loading and electroporation approach, after sonication significantly fewer CD9+ EVs/mL (p < 0.001) and CD63+ EVs/mL (p < 0.001) existed, as determined by IFCM. This observation indicates that sonication, in particular, may have detrimental effects on EVs. In conclusion, EVs can be successfully separated from both MSC CM and milk, with milk being a particularly rich source. Of the three methods tested, electroporation appears to be superior for achieving maximum drug loading while not causing damage to EV surface proteins. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessArticle

Biodistribution of Intratracheal, Intranasal, and Intravenous Injections of Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles in a Mouse Model for Drug Delivery Studies

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Pharmaceutics 2023, 15(2), 548; https://doi.org/10.3390/pharmaceutics15020548 - 07 Feb 2023

Viewed by 691

Abstract

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are extensively studied as therapeutic tools. Evaluation of their biodistribution is fundamental to understanding MSC-EVs’ impact on target organs. In our work, MSC-EVs were initially labeled with DiR, a fluorescent lipophilic dye, and administered to BALB/c mice [...] Read more.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are extensively studied as therapeutic tools. Evaluation of their biodistribution is fundamental to understanding MSC-EVs’ impact on target organs. In our work, MSC-EVs were initially labeled with DiR, a fluorescent lipophilic dye, and administered to BALB/c mice (2.00 × 10¹⁰ EV/mice) through the following routes: intravenous (IV), intratracheal (IT) and intranasal (IN). DiR-labeled MSC-EVs were monitored immediately after injection, and after 3 and 24 hours (h). Whole-body analysis, 3 h after IV injection, showed an accumulation of MSC-EVs in the mice abdominal region, compared to IT and IN, where EVs mainly localized at the levels of the chest and brain region, respectively. After 24 h, EV-injected mice retained a stronger positivity in the same regions identified after 3 h from injection. The analyses of isolated organs confirmed the accumulation of EVs in the spleen and liver after IV administration. Twenty-four hours after the IT injection of MSC-EVs, a stronger positivity was detected selectively in the isolated lungs, while for IN, the signal was confined to the brain. In conclusion, these results show that local administration of EVs can increase their concentration in selective organs, limiting their systemic biodistribution and possibly the extra-organ effects. Biodistribution studies can help in the selection of the most appropriate way of administration of MSC-EVs for the treatment of different diseases. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessArticle

CCR7 Mediates Dendritic-Cell-Derived Exosome Migration and Improves Cardiac Function after Myocardial Infarction

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Pharmaceutics 2023, 15(2), 461; https://doi.org/10.3390/pharmaceutics15020461 - 30 Jan 2023

Viewed by 578

Abstract

Dendritic cells (DCs) play key roles in promoting wound healing after myocardial infarction (MI). Our previous studies have shown that exosomes derived from DCs (DEXs) could migrate to lymphoid tissue and improve cardiac function post-MI by activating CD4⁺ T cells; however, the [...] Read more.

Dendritic cells (DCs) play key roles in promoting wound healing after myocardial infarction (MI). Our previous studies have shown that exosomes derived from DCs (DEXs) could migrate to lymphoid tissue and improve cardiac function post-MI by activating CD4⁺ T cells; however, the mechanism of DEXs’ migration to lymphoid tissue and the improvement of cardiac function are still unknown. In our study, we found that CCR7 expression significantly increased in MI-DEXs compared with control-DEXs; meanwhile, CCL19 and CCL21, the ligands of CCR7, significantly increased in the serum of MI-model mice. Subsequently, we overexpressed and knocked down CCR7 in MI-DEXs and found that overexpressed CCR7 enhanced the migration of MI-DEXs to the spleen; however, CCR7 knockdown attenuated MI-DEXs’ migration according to near-IR fluorescence imaging. Furthermore, overexpressed CCR7 in MI-DEXs enhanced the MI-DEXs’ improvement of cardiac function after MI; however, CCR7-knockdown MI-DEXs attenuated this improvement. In addition, after DEXs’ migration to the spleen, MI-DEXs activated CD4⁺ T cells and induced the expression of IL-4 and IL-10, which were significantly increased in the MI-DEX group compared with the control group. In conclusion, CCR7 could mediate DEXs’ migration to the spleen and improve cardiac function after MI, and we found that the mechanism was partly via activation of CD4⁺ T cells and secretion of IL-4 and IL-10. Our study presented an innovative method for improving cardiac function by enhancing the migration ability of MI-DEXs after MI, while CCR7 could be a potential candidate for MI-DEX bioengineering to enhance migration. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessArticle

Genetically Engineered Extracellular Vesicles Harboring Transmembrane Scaffolds Exhibit Differences in Their Size, Expression Levels of Specific Surface Markers and Cell-Uptake

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Pharmaceutics 2022, 14(12), 2564; https://doi.org/10.3390/pharmaceutics14122564 - 23 Nov 2022

Cited by 1 | Viewed by 1094

Abstract

Background: Human cell-secreted extracellular vesicles (EVs) are versatile nanomaterials suitable for disease-targeted drug delivery and therapy. Native EVs, however, usually do not interact specifically with target cells or harbor therapeutic drugs, which limits their potential for clinical applications. These functions can be introduced [...] Read more.

Background: Human cell-secreted extracellular vesicles (EVs) are versatile nanomaterials suitable for disease-targeted drug delivery and therapy. Native EVs, however, usually do not interact specifically with target cells or harbor therapeutic drugs, which limits their potential for clinical applications. These functions can be introduced to EVs by genetic manipulation of membrane protein scaffolds, although the efficiency of these manipulations and the impacts they have on the properties of EVs are for the most part unknown. In this study, we quantify the effects of genetic manipulations of different membrane scaffolds on the physicochemical properties, molecular profiles, and cell uptake of the EVs. Methods: Using a combination of gene fusion, molecular imaging, and immuno-based on-chip analysis, we examined the effects of various protein scaffolds, including endogenous tetraspanins (CD9, CD63, and CD81) and exogenous vesicular stomatitis virus glycoprotein (VSVG), on the efficiency of integration in EV membranes, the physicochemical properties of EVs, and EV uptake by recipient cells. Results: Fluorescence imaging and live cell monitoring showed each scaffold type was integrated into EVs either in membranes of the endocytic compartment, the plasma membrane, or both. Analysis of vesicle size revealed that the incorporation of each scaffold increased the average diameter of vesicles compared to unmodified EVs. Molecular profiling of surface markers in engineered EVs using on-chip assays showed the CD63-GFP scaffold decreased expression of CD81 on the membrane surface compared to control EVs, whereas its expression was mostly unchanged in EVs bearing CD9-, CD81-, or VSVG-GFP. The results from cell uptake studies demonstrated that VSVG-engineered EVs were taken up by recipient cells to a greater degree than control EVs. Conclusion: We found that the incorporation of different molecular scaffolds in EVs altered their physicochemical properties, surface protein profiles, and cell-uptake functions. Scaffold-induced changes in the physical and functional properties of engineered EVs should therefore be considered in engineering EVs for the targeted delivery and uptake of therapeutics to diseased cells. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Review

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Open AccessReview

Bacterial Membrane Vesicles as Smart Drug Delivery and Carrier Systems: A New Nanosystems Tool for Current Anticancer and Antimicrobial Therapy

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Ceyda Tuba Sengel-Türk

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Burak Derkus

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Ahmet Çabuk

Pharmaceutics 2023, 15(4), 1052; https://doi.org/10.3390/pharmaceutics15041052 - 24 Mar 2023

Viewed by 270

Abstract

Bacterial membrane vesicles (BMVs) are known to be critical communication tools in several pathophysiological processes between bacteria and host cells. Given this situation, BMVs for transporting and delivering exogenous therapeutic cargoes have been inspiring as promising platforms for developing smart drug delivery systems [...] Read more.

Bacterial membrane vesicles (BMVs) are known to be critical communication tools in several pathophysiological processes between bacteria and host cells. Given this situation, BMVs for transporting and delivering exogenous therapeutic cargoes have been inspiring as promising platforms for developing smart drug delivery systems (SDDSs). In the first section of this review paper, starting with an introduction to pharmaceutical technology and nanotechnology, we delve into the design and classification of SDDSs. We discuss the characteristics of BMVs including their size, shape, charge, effective production and purification techniques, and the different methods used for cargo loading and drug encapsulation. We also shed light on the drug release mechanism, the design of BMVs as smart carriers, and recent remarkable findings on the potential of BMVs for anticancer and antimicrobial therapy. Furthermore, this review covers the safety of BMVs and the challenges that need to be overcome for clinical use. Finally, we discuss the recent advancements and prospects for BMVs as SDDSs and highlight their potential in revolutionizing the fields of nanomedicine and drug delivery. In conclusion, this review paper aims to provide a comprehensive overview of the state-of-the-art field of BMVs as SDDSs, encompassing their design, composition, fabrication, purification, and characterization, as well as the various strategies used for targeted delivery. Considering this information, the aim of this review is to provide researchers in the field with a comprehensive understanding of the current state of BMVs as SDDSs, enabling them to identify critical gaps and formulate new hypotheses to accelerate the progress of the field. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

The CRISPR/Cas9 System Delivered by Extracellular Vesicles

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Pharmaceutics 2023, 15(3), 984; https://doi.org/10.3390/pharmaceutics15030984 - 18 Mar 2023

Viewed by 417

Abstract

Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems can precisely manipulate DNA sequences to change the characteristics of cells and organs, which has potential in the mechanistic research on genes and the treatment of diseases. However, clinical applications are restricted by [...] Read more.

Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems can precisely manipulate DNA sequences to change the characteristics of cells and organs, which has potential in the mechanistic research on genes and the treatment of diseases. However, clinical applications are restricted by the lack of safe, targeted and effective delivery vectors. Extracellular vesicles (EVs) are an attractive delivery platform for CRISPR/Cas9. Compared with viral and other vectors, EVs present several advantages, including safety, protection, capacity, penetrating ability, targeting ability and potential for modification. Consequently, EVs are profitably used to deliver the CRISPR/Cas9 in vivo. In this review, the advantages and disadvantages of the delivery form and vectors of the CRISPR/Cas9 are concluded. The favorable traits of EVs as vectors, such as the innate characteristics, physiological and pathological functions, safety and targeting ability of EVs, are summarized. Furthermore, in terms of the delivery of the CRISPR/Cas9 by EVs, EV sources and isolation strategies, the delivery form and loading methods of the CRISPR/Cas9 and applications have been concluded and discussed. Finally, this review provides future directions of EVs as vectors of the CRISPR/Cas9 system in clinical applications, such as the safety, capacity, consistent quality, yield and targeting ability of EVs. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Extracellular Vesicles as Drug Delivery Systems in Organ Transplantation: The Next Frontier

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Harry V. M. Spiers

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Lukas K. J. Stadler

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Hugo Smith

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Vasilis Kosmoliaptsis

Pharmaceutics 2023, 15(3), 891; https://doi.org/10.3390/pharmaceutics15030891 - 09 Mar 2023

Viewed by 544

Abstract

Extracellular vesicles are lipid bilayer-delimited nanoparticles excreted into the extracellular space by all cells. They carry a cargo rich in proteins, lipids and DNA, as well as a full complement of RNA species, which they deliver to recipient cells to induce downstream signalling, [...] Read more.

Extracellular vesicles are lipid bilayer-delimited nanoparticles excreted into the extracellular space by all cells. They carry a cargo rich in proteins, lipids and DNA, as well as a full complement of RNA species, which they deliver to recipient cells to induce downstream signalling, and they play a key role in many physiological and pathological processes. There is evidence that native and hybrid EVs may be used as effective drug delivery systems, with their intrinsic ability to protect and deliver a functional cargo by utilising endogenous cellular mechanisms making them attractive as therapeutics. Organ transplantation is the gold standard for treatment for suitable patients with end-stage organ failure. However, significant challenges still remain in organ transplantation; prevention of graft rejection requires heavy immunosuppression and the lack of donor organs results in a failure to meet demand, as manifested by growing waiting lists. Pre-clinical studies have demonstrated the ability of EVs to prevent rejection in transplantation and mitigate ischemia reperfusion injury in several disease models. The findings of this work have made clinical translation of EVs possible, with several clinical trials actively recruiting patients. However, there is much to be uncovered, and it is essential to understand the mechanisms behind the therapeutic benefits of EVs. Machine perfusion of isolated organs provides an unparalleled platform for the investigation of EV biology and the testing of the pharmacokinetic and pharmacodynamic properties of EVs. This review classifies EVs and their biogenesis routes, and discusses the isolation and characterisation methods adopted by the international EV research community, before delving into what is known about EVs as drug delivery systems and why organ transplantation represents an ideal platform for their development as drug delivery systems. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Oral Administration as a Potential Alternative for the Delivery of Small Extracellular Vesicles

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Darío Donoso-Meneses

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Aliosha I. Figueroa-Valdés

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Maroun Khoury

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Francisca Alcayaga-Miranda

Pharmaceutics 2023, 15(3), 716; https://doi.org/10.3390/pharmaceutics15030716 - 21 Feb 2023

Viewed by 330

Abstract

Small extracellular vesicles (sEVs) have burst into biomedicine as a natural therapeutic alternative for different diseases. Considered nanocarriers of biological origin, various studies have demonstrated the feasibility of their systemic administration, even with repeated doses. However, despite being the preferred route of physicians [...] Read more.

Small extracellular vesicles (sEVs) have burst into biomedicine as a natural therapeutic alternative for different diseases. Considered nanocarriers of biological origin, various studies have demonstrated the feasibility of their systemic administration, even with repeated doses. However, despite being the preferred route of physicians and patients, little is known about the clinical use of sEVs in oral administration. Different reports show that sEVs can resist the degradative conditions of the gastrointestinal tract after oral administration, accumulating regionally in the intestine, where they are absorbed for systemic biodistribution. Notably, observations demonstrate the efficacy of using sEVs as a nanocarrier system for a therapeutic payload to obtain a desired biological (therapeutic) effect. From another perspective, the information to date indicates that food-derived vesicles (FDVs) could be considered future nutraceutical agents since they contain or even overexpress different nutritional compounds of the foods from which they are derived, with potential effects on human health. In this review, we present and critically analyze the current information on the pharmacokinetics and safety profile of sEVs when administered orally. We also address the molecular and cellular mechanisms that promote intestinal absorption and that command the therapeutic effects that have been observed. Finally, we analyze the potential nutraceutical impact that FDVs would have on human health and how their oral use could be an emerging strategy to balance nutrition in people. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Production and Utility of Extracellular Vesicles with 3D Culture Methods

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Mar Casajuana Ester

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Richard M. Day

Pharmaceutics 2023, 15(2), 663; https://doi.org/10.3390/pharmaceutics15020663 - 16 Feb 2023

Viewed by 789

Abstract

In recent years, extracellular vesicles (EVs) have emerged as promising biomarkers, cell-free therapeutic agents, and drug delivery carriers. Despite their great clinical potential, poor yield and unscalable production of EVs remain significant challenges. When using 3D culture methods, such as scaffolds and bioreactors, [...] Read more.

In recent years, extracellular vesicles (EVs) have emerged as promising biomarkers, cell-free therapeutic agents, and drug delivery carriers. Despite their great clinical potential, poor yield and unscalable production of EVs remain significant challenges. When using 3D culture methods, such as scaffolds and bioreactors, large numbers of cells can be expanded and the cell environment can be manipulated to control the cell phenotype. This has been employed to successfully increase the production of EVs as well as to enhance their therapeutic effects. The physiological relevance of 3D cultures, such as spheroids, has also provided a strategy for understanding the role of EVs in the pathogenesis of several diseases and to evaluate their role as tools to deliver drugs. Additionally, 3D culture methods can encapsulate EVs to achieve more sustained therapeutic effects as well as prevent premature clearance of EVs to enable more localised delivery and concentrated exosome dosage. This review highlights the opportunities and drawbacks of different 3D culture methods and their use in EV research. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Extracellular Vesicles of Probiotics: Shedding Light on the Biological Activity and Future Applications

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Pharmaceutics 2023, 15(2), 522; https://doi.org/10.3390/pharmaceutics15020522 - 04 Feb 2023

Viewed by 653

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For many decades, the proper functioning of the human body has become a leading scientific topic. In the course of numerous experiments, a striking impact of probiotics on the human body has been documented, including maintaining the physiological balance of endogenous microorganisms, regulating [...] Read more.

For many decades, the proper functioning of the human body has become a leading scientific topic. In the course of numerous experiments, a striking impact of probiotics on the human body has been documented, including maintaining the physiological balance of endogenous microorganisms, regulating the functioning of the immune system, enhancing the digestive properties of the host, and preventing or alleviating the course of many diseases. Recent research, especially from the last decade, shows that this health-benefiting activity of probiotics is largely conditioned by the production of extracellular vesicles. Although the importance of extracellular vesicles in the virulence of many live-threatening pathogens is widely described in the literature, much less is known with respect to the health-promoting effect of extracellular vesicles secreted by non-pathogenic microorganisms, including probiotics. Based on this, in the current review article, we decided to collect the latest literature data on the health-inducing properties of extracellular vesicles secreted by probiotics. The characteristics of probiotics’ extracellular vesicles will be extended by the description of their physicochemical properties and the proteome in connection with the biological activities exhibited by these structures. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Bio-Inspired Drug Delivery Systems: From Synthetic Polypeptide Vesicles to Outer Membrane Vesicles

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Pharmaceutics 2023, 15(2), 368; https://doi.org/10.3390/pharmaceutics15020368 - 21 Jan 2023

Viewed by 659

Abstract

Nanomedicine is a broad field that focuses on the development of nanocarriers to deliver specific drugs to targeted sites. A synthetic polypeptide is a kind of biomaterial composed of repeating amino acid units that are linked by peptide bonds. The multiplied amphiphilicity segment [...] Read more.

Nanomedicine is a broad field that focuses on the development of nanocarriers to deliver specific drugs to targeted sites. A synthetic polypeptide is a kind of biomaterial composed of repeating amino acid units that are linked by peptide bonds. The multiplied amphiphilicity segment of the polypeptide could assemble to form polypeptide vesicles (PVs) under suitable conditions. Different from polypeptide vesicles, outer membrane vesicles (OMVs) are spherical buds of the outer membrane filled with periplasmic content, which commonly originate from Gram-negative bacteria. Owing to their biodegradability and excellent biocompatibility, both PVs and OMVs have been utilized as carriers in delivering drugs. In this review, we discuss the recent drug delivery research based on PVs and OMVs. These related topics are presented: (1) a brief introduction to the production methods for PVs and OMVs; (2) a thorough explanation of PV- and OMV-related applications in drug delivery including the vesicle design and biological assessment; (3) finally, we conclude with a discussion on perspectives and future challenges related to the drug delivery systems of PVs and OMVs. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Extracellular Vesicles as New Players in Drug Delivery: A Focus on Red Blood Cells-Derived EVs

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Pharmaceutics 2023, 15(2), 365; https://doi.org/10.3390/pharmaceutics15020365 - 21 Jan 2023

Viewed by 966

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The article is divided into several sections, focusing on extracellular vesicles’ (EVs) nature, features, commonly employed methodologies and strategies for their isolation/preparation, and their characterization/visualization. This work aims to give an overview of advances in EVs’ extensive nanomedical-drug delivery applications. Furthermore, considerations for [...] Read more.

The article is divided into several sections, focusing on extracellular vesicles’ (EVs) nature, features, commonly employed methodologies and strategies for their isolation/preparation, and their characterization/visualization. This work aims to give an overview of advances in EVs’ extensive nanomedical-drug delivery applications. Furthermore, considerations for EVs translation to clinical application are summarized here, before focusing the review on a special kind of extracellular vesicles, the ones derived from red blood cells (RBCEVs). Generally, employing EVs as drug carriers means managing entities with advantageous properties over synthetic vehicles or nanoparticles. Besides the fact that certain EVs also reveal intrinsic therapeutic characteristics, in regenerative medicine, EVs nanosize, lipidomic and proteomic profiles enable them to pass biologic barriers and display cell/tissue tropisms; indeed, EVs engineering can further optimize their organ targeting. In the second part of the review, we focus our attention on RBCEVs. First, we describe the biogenesis and composition of those naturally produced by red blood cells (RBCs) under physiological and pathological conditions. Afterwards, we discuss the current procedures to isolate and/or produce RBCEVs in the lab and to load a specific cargo for therapeutic exploitation. Finally, we disclose the most recent applications of RBCEVs at the in vitro and preclinical research level and their potential industrial exploitation. In conclusion, RBCEVs can be, in the near future, a very promising and versatile platform for several clinical applications and pharmaceutical exploitations. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Advances in the Study of Exosomes as Drug Delivery Systems for Bone-Related Diseases

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Pharmaceutics 2023, 15(1), 220; https://doi.org/10.3390/pharmaceutics15010220 - 09 Jan 2023

Viewed by 805

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Bone-related diseases are major problems and heavy burdens faced by modern society. Current clinical approaches for the treatment of these pathological conditions often lead to complications and have limited therapeutic efficacy. In this context, the development of nanotherapeutic platforms, such as extracellular vesicles, [...] Read more.

Bone-related diseases are major problems and heavy burdens faced by modern society. Current clinical approaches for the treatment of these pathological conditions often lead to complications and have limited therapeutic efficacy. In this context, the development of nanotherapeutic platforms, such as extracellular vesicles, can improve the relevant therapeutic effects. In particular, exosomes are nano-sized, lipid bilayer extracellular vesicles secreted by many cells in mammals. Due to their innate capacity to transport materials—including proteins, lipids, and genes—among cells, as well as their innate attraction to target cells, they are considered to be a crucial medium for cell communication and are involved in a number of biological processes. Exosomes have been used as drug delivery vehicles in recent bone tissue engineering studies, in order to regulate bone homeostasis. However, the precise workings of the exosome regulatory network in maintaining bone homeostasis and its potential for treating bone injury remain unclear. To provide a fresh perspective for the study of exosomes in drug delivery and bone-related diseases, in this paper, we review recent studies on the roles of exosomes for drug delivery in bone homeostasis and bone-related diseases, as well as the composition and characteristics of exosomes and their regulatory roles in bone homeostasis and bone-related diseases, aiming to provide new ideas for the therapeutic application of exosomes in the treatment of bone-related diseases. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Extracellular Non-Coding RNAs in Cardiovascular Diseases

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Pharmaceutics 2023, 15(1), 155; https://doi.org/10.3390/pharmaceutics15010155 - 03 Jan 2023

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Cardiovascular diseases (CVDs) remain the world’s leading cause of death despite the best available healthcare and therapy. Emerging as a key mediator of intercellular and inter-organ communication in CVD pathogenesis, extracellular vesicles (EVs) are a heterogeneous group of membrane-enclosed nano-sized vesicles released by [...] Read more.

Cardiovascular diseases (CVDs) remain the world’s leading cause of death despite the best available healthcare and therapy. Emerging as a key mediator of intercellular and inter-organ communication in CVD pathogenesis, extracellular vesicles (EVs) are a heterogeneous group of membrane-enclosed nano-sized vesicles released by virtually all cells, of which their RNA cargo, especially non-coding RNAs (ncRNA), has been increasingly recognized as a promising diagnostic and therapeutic target. Recent evidence shows that ncRNAs, such as small ncRNAs, circular RNAs, and long ncRNAs, can be selectively sorted into EVs or other non-vesicular carriers and modulate various biological processes in recipient cells. In this review, we summarize recent advances in the literature regarding the origin, extracellular carrier, and functional mechanisms of extracellular ncRNAs with a focus on small ncRNAs, circular RNAs, and long ncRNAs. The pathophysiological roles of extracellular ncRNAs in various CVDs, including atherosclerosis, ischemic heart diseases, hypertension, cardiac hypertrophy, and heart failure, are extensively discussed. We also provide an update on recent developments and challenges in using extracellular ncRNAs as biomarkers or therapeutical targets in these CVDs. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Engineered Exosomes for Tumor-Targeted Drug Delivery: A Focus on Genetic and Chemical Functionalization

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Ali Akbari

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Fereshteh Nazari-Khanamiri

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Mahdi Ahmadi

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Maryam Shoaran

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Jafar Rezaie

Pharmaceutics 2023, 15(1), 66; https://doi.org/10.3390/pharmaceutics15010066 - 26 Dec 2022

Viewed by 1119

Abstract

Cancer is the main cause of death worldwide. The limitations in traditional cancer therapies provoked the advance and use of several nanotechnologies for more effective and nontoxic cancer treatment. Along with synthetic nanocarriers, extracellular vesicles (EVs)-mediated drug delivery systems have aroused substantial interest. [...] Read more.

Cancer is the main cause of death worldwide. The limitations in traditional cancer therapies provoked the advance and use of several nanotechnologies for more effective and nontoxic cancer treatment. Along with synthetic nanocarriers, extracellular vesicles (EVs)-mediated drug delivery systems have aroused substantial interest. The term EVs refers to cell-derived nanovesicles, such as exosomes, with phospholipid-bound structures, participating in cell-to-cell communication. Exosomes are 30–150 nm vesicles that can transfer many biological molecules between cells. From a drug delivery standpoint, exosomes can be loaded with various therapeutic cargo, with the several advantages of low immunogenicity, high biocompatibility, transformative, and effective tumor targeting aptitude. The exosomal surface can be functionalized to improve tumor targeting ability of them. Researchers have genetically expressed or chemically linked various molecules on the surface of exosomes. Despite extensive investigation, clinical translation of exosome-based drug delivery remains challenging. In this review, we discuss various methods used to loading exosomes with therapeutic cargo. We describe examples of functionalized exosomes surface using genetic and chemical modification methods. Finally, this review attempts to provide future outlooks for exosome-based targeted drug delivery. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System

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Pharmaceutics 2023, 15(1), 21; https://doi.org/10.3390/pharmaceutics15010021 - 21 Dec 2022

Viewed by 854

Abstract

Drug delivery system (DDS) realizes the drug delivery process through the drug carrier. As an important part of DDS, the selection of the drug carrier material is extremely critical, which requires the carrier material to possess excellent biocompatibility and targeting and not affect [...] Read more.

Drug delivery system (DDS) realizes the drug delivery process through the drug carrier. As an important part of DDS, the selection of the drug carrier material is extremely critical, which requires the carrier material to possess excellent biocompatibility and targeting and not affect the pharmacological action of the drug. As one of the endogenous extracellular vesicles, exosomes are 30–100 nm in diameter, which are considered a new generation of a natural nanoscale delivery system. Exosomes secreted by different types of cells carry signaling molecules (such as proteins and nucleic acid) playing an important role in cell behaviors. Owing to their ability to specialize in intercellular communication, exosomes provide a distinctive method to deliver therapeutic drugs to target cells. In this concept, exosomes as the natural liposomes carry endogenous biomolecules, have excellent biocompatibility, and could be loaded with cargo both in vivo and in vitro. In addition, modifications by genetic and/or chemical engineering to part of the exosome surface or complement the desired natural effect may enhance the targeting with drug loading capability. Notably, exosomes weakly react with serum proteins prolonging cargo half-life. Overall, exosomes as natural carriers integrate the superiority of synthetic nanocarriers and cellular communication while precluding their limitations, which provides novel and reliable methods for drug delivery and treatment. Our review focuses on the therapeutic potentials and clinical values of exosomes as a carrier of drug delivery system in multiple diseases, including cancer, nervous, immune, and skeletal system diseases. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Extracellular Vesicle-Based Therapeutics in Neurological Disorders

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Pharmaceutics 2022, 14(12), 2652; https://doi.org/10.3390/pharmaceutics14122652 - 30 Nov 2022

Cited by 2 | Viewed by 916

Abstract

Neurological diseases remain some of the major causes of death and disability in the world. Few types of drugs and insufficient delivery across the blood–brain barrier limit the treatment of neurological disorders. The past two decades have seen the rapid development of extracellular [...] Read more.

Neurological diseases remain some of the major causes of death and disability in the world. Few types of drugs and insufficient delivery across the blood–brain barrier limit the treatment of neurological disorders. The past two decades have seen the rapid development of extracellular vesicle-based therapeutics in many fields. As the physiological and pathophysiological roles of extracellular vesicles are recognized in neurological diseases, they have become promising therapeutics and targets for therapeutic interventions. Moreover, advanced nanomedicine technologies have explored the potential of extracellular vesicles as drug delivery systems in neurological diseases. In this review, we discussed the preclinical strategies for extracellular vesicle-based therapeutics in neurological disorders and the struggles involved in their clinical application. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Phospholipid-Membrane-Based Nanovesicles Acting as Vaccines for Tumor Immunotherapy: Classification, Mechanisms and Applications

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Pharmaceutics 2022, 14(11), 2446; https://doi.org/10.3390/pharmaceutics14112446 - 11 Nov 2022

Cited by 1 | Viewed by 867

Abstract

Membrane vesicles, a group of nano- or microsized vesicles, can be internalized or interact with the recipient cells, depending on their parental cells, size, structure and content. Membrane vesicles fuse with the target cell membrane, or they bind to the receptors on the [...] Read more.

Membrane vesicles, a group of nano- or microsized vesicles, can be internalized or interact with the recipient cells, depending on their parental cells, size, structure and content. Membrane vesicles fuse with the target cell membrane, or they bind to the receptors on the cell surface, to transfer special effects. Based on versatile features, they can modulate the functions of immune cells and therefore influence immune responses. In the field of tumor therapeutic applications, phospholipid-membrane-based nanovesicles attract increased interest. Academic institutions and industrial companies are putting in effort to design, modify and apply membrane vesicles as potential tumor vaccines contributing to tumor immunotherapy. This review focuses on the currently most-used types of membrane vesicles (including liposomes, bacterial membrane vesicles, tumor- and dendritic-cell-derived extracellular vesicles) acting as tumor vaccines, and describes the classification, mechanism and application of these nanovesicles. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Open AccessReview

Membrane Vesicles Derived from Gut Microbiota and Probiotics: Cutting-Edge Therapeutic Approaches for Multidrug-Resistant Superbugs Linked to Neurological Anomalies

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Prakhar Srivastava

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Kwang-sun Kim

Pharmaceutics 2022, 14(11), 2370; https://doi.org/10.3390/pharmaceutics14112370 - 03 Nov 2022

Cited by 2 | Viewed by 1362

Abstract

Multidrug-resistant (MDR) superbugs can breach the blood–brain barrier (BBB), leading to a continuous barrage of pro-inflammatory modulators and induction of severe infection-related pathologies, including meningitis and brain abscess. Both broad-spectrum or species-specific antibiotics (β-lactamase inhibitors, polymyxins, vancomycin, meropenem, plazomicin, and sarecycline) and biocompatible [...] Read more.

Multidrug-resistant (MDR) superbugs can breach the blood–brain barrier (BBB), leading to a continuous barrage of pro-inflammatory modulators and induction of severe infection-related pathologies, including meningitis and brain abscess. Both broad-spectrum or species-specific antibiotics (β-lactamase inhibitors, polymyxins, vancomycin, meropenem, plazomicin, and sarecycline) and biocompatible poly (lactic-co-glycolic acid) (PLGA) nanoparticles have been used to treat these infections. However, new therapeutic platforms with a broad impact that do not exert off-target deleterious effects are needed. Membrane vesicles or extracellular vesicles (EVs) are lipid bilayer-enclosed particles with therapeutic potential owing to their ability to circumvent BBB constraints. Bacteria-derived EVs (bEVs) from gut microbiota are efficient transporters that can penetrate the central nervous system. In fact, bEVs can be remodeled via surface modification and CRISPR/Cas editing and, thus, represent a novel platform for conferring protection against infections breaching the BBB. Here, we discuss the latest scientific research related to gut microbiota- and probiotic-derived bEVs, and their therapeutic modifications, in terms of regulating neurotransmitters and inhibiting quorum sensing, for the treatment of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. We also emphasize the benefits of probiotic-derived bEVs to human health and propose a novel direction for the development of innovative heterologous expression systems to combat BBB-crossing pathogens. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Exosomes as CNS Drug Delivery Tools and Their Applications

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Pharmaceutics 2022, 14(10), 2252; https://doi.org/10.3390/pharmaceutics14102252 - 21 Oct 2022

Cited by 6 | Viewed by 1592

Abstract

Central nervous system (CNS) diseases threaten the health of people all over the world. However, due to the structural and functional particularities of the brain and spinal cord, CNS-targeted drug development is rather challenging. Exosomes are small cellular vesicles with lipid bilayers that [...] Read more.

Central nervous system (CNS) diseases threaten the health of people all over the world. However, due to the structural and functional particularities of the brain and spinal cord, CNS-targeted drug development is rather challenging. Exosomes are small cellular vesicles with lipid bilayers that can be secreted by almost all cells and play important roles in intercellular communication. The advantages of low immunogenicity, the ability to cross the blood-brain barrier, and the flexibility of drug encapsulation make them stand out among CNS drug delivery tools. Herein, we reviewed the research on exosomes in CNS drug delivery over the past decade and outlined the impact of the drug loading mode, administration route, and engineered modification on CNS targeting. Finally, we highlighted the problems and prospects of exosomes as CNS drug delivery tools. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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Extracellular Vesicles: A New Frontier for Cardiac Repair

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Pharmaceutics 2022, 14(9), 1848; https://doi.org/10.3390/pharmaceutics14091848 - 01 Sep 2022

Cited by 2 | Viewed by 1596

Abstract

The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been used to treat diseases. Growing evidence indicates that EVs play a cardioprotective role in heart disease by activating beneficial signaling pathways. Multiple functional components of EVs [...] Read more.

The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been used to treat diseases. Growing evidence indicates that EVs play a cardioprotective role in heart disease by activating beneficial signaling pathways. Multiple functional components of EVs and intracellular molecular mechanisms are involved in the process. To overcome the shortcomings of native EVs such as their heterogeneity and limited tropism, a series of engineering approaches has been developed to improve the therapeutic efficiency of EVs. In this review, we present an overview of the research and future directions for EVs-based cardiac therapies with an emphasis on EVs-mediated delivery of therapeutic agents. The advantages and limitations of various modification strategies are discussed, and possible opportunities for improvement are proposed. An in-depth understanding of the endogenous properties of EVs and EVs engineering strategies could lead to a promising cell-free therapy for cardiac repair. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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