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Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 42136

Special Issue Editor

Dr. Arnaud Bianchi

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Guest Editor
Molecular Engineering and Articular Physiopathology (IMoPA), French National Center for Scientific Research (CNRS), Université de Lorraine, 54000 Nancy, France
Interests: natural products; bioactive compounds; phenolics; plant derived compounds; medicinal plants; natural products chemistry; pre-formulation; hydrogel; wound healing; nanoparticle; cartilage; osteoarthritis; ectopic mineralization; liposomes; extracellular vesicles; biomaterials; nuclear receptors; oxidant stress; cellular signalisation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Vesicles are becoming significant drug delivery systems thanks to their capability to target specific tissues and cells to deliver bioactive molecules.

Liposomes are vesicles that stand out among different types of self-assembled vesicles, because of their amphiphilicity and their cytocompatibility. Moreover, man-made liposomes have a controllable lipid composition that favors the reuse of biosources from plant or animal sources.

Mesenchymal stem cells (MSCs) are used as therapeutic agents in cell-based therapy for inflammatory and degenerative diseases. A large number of experimental and clinical studies revealed that most MSC-mediated healing effects were attributed to the extracellular vesicles (EVs) they secrete. Recent studies showed that engineered EVs with surface modifications are appropriated tools for targeted drug delivery.

In addition to synthetic vesicles and EVs, “smarter” delivery systems can be engineered by creating hybrid EV-liposome carriers via membrane fusion. All these systems can be loaded in hydrogels to achieve sustained and controlled drug delivery.

Many challenges related to liposomes, EVs, and hybrid systems persist. For example, liposomes are still considered the most successful family of vesicular vectors within the field of medicine. However, after 60 years of research, their full potential has yet to be achieved, as only a trickle of liposomal drug formulations have reached the market. Going forward, engineering targeted controlled drug delivery systems is of major importance and can achieve a huge breakthrough in treating many diseases.

Therefore, this Special Issue of IJMS will focus on the advances of vesicular vectors in the field of medicine over the last 10 years, and how this can reinforce the development of new therapeutics. It will also emphasize critical problems and their resolutions: cytotoxic effects, leakage, stability problems, batch to batch reproducibility, effective sterilization methods, and scale-up impediments. Our aim is for this Special Issue to shine a light on multidisciplinary research that examines these developments.

Dr. Arnaud Bianchi
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • liposomes
  • extracellular vesicles
  • vectorization
  • drug delivery
  • targeting
  • regenerative medicine

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Published Papers (10 papers)

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Editorial

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5 pages, 192 KiB  
Editorial
Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?
by Émilie Velot and Arnaud Bianchi
Int. J. Mol. Sci. 2024, 25(6), 3530; https://doi.org/10.3390/ijms25063530 - 20 Mar 2024
Viewed by 735
Abstract
Extracellular vesicles (EVs) are membrane-enclosed particles released by cells into their extracellular environment [...] Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)

Research

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10 pages, 614 KiB  
Article
Shock-Driven Endotheliopathy in Trauma Patients Is Associated with Leucocyte Derived Extracellular Vesicles
by Romein W. G. Dujardin, Jeske E. C. Kisters, Mathijs R. Wirtz, Najat Hajji, Anita M. Tuip-de Boer, Jakob Stensballe, Pär I. Johansson, Karim Brohi, Ross A. Davenport, Christine Gaarder, Simon Stanworth, Marc Maegele, Rienk Nieuwland, Edwin van der Pol and Nicole P. Juffermans
Int. J. Mol. Sci. 2022, 23(24), 15990; https://doi.org/10.3390/ijms232415990 - 15 Dec 2022
Cited by 2 | Viewed by 2067
Abstract
Endotheliopathy following trauma is associated with poor outcome, but the underlying mechanisms are unknown. This study hypothesized that an increased extracellular vesicle (EV) concentration is associated with endotheliopathy after trauma and that red blood cell (RBC) transfusion could further enhance endotheliopathy. In this [...] Read more.
Endotheliopathy following trauma is associated with poor outcome, but the underlying mechanisms are unknown. This study hypothesized that an increased extracellular vesicle (EV) concentration is associated with endotheliopathy after trauma and that red blood cell (RBC) transfusion could further enhance endotheliopathy. In this post hoc sub study of a multicentre observational trial, 75 trauma patients were stratified into three groups based on injury severity score or shock. In patient plasma obtained at hospital admission and after transfusion of four RBC transfusions, markers for endotheliopathy were measured and EVs were labelled with anti CD41 (platelet EVs), anti CD235a (red blood cell EVs), anti CD45 (leucocyte EVs), anti CD144 (endothelial EVs) or anti CD62e (activated endothelial EVs) and EV concentrations were measured with flow cytometry. Statistical analysis was performed by a Kruskall Wallis test with Bonferroni correction or Wilcoxon rank test for paired data. In patients with shock, syndecan-1 and von Willebrand Factor (vWF) were increased compared to patients without shock. Additionally, patients with shock had increased red blood cell EV and leucocyte EV concentrations compared to patients without shock. Endotheliopathy markers correlated with leucocyte EVs (ρ = 0.263, p = 0.023), but not with EVs derived from other cells. Injury severity score had no relation with EV release. RBC transfusion increased circulating red blood cell EVs but did not impact endotheliopathy. In conclusion, shock is (weakly) associated with EVs from leucocytes, suggesting an immune driven pathway mediated (at least in part) by shock. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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15 pages, 2052 KiB  
Article
Lim Domain Binding 3 (Ldb3) Identified as a Potential Marker of Cardiac Extracellular Vesicles
by Fadi Abou Zeid, Henri Charrier, Olivia Beseme, Jean-Baptiste Michel, Paul Mulder, Philippe Amouyel, Florence Pinet and Annie Turkieh
Int. J. Mol. Sci. 2022, 23(13), 7374; https://doi.org/10.3390/ijms23137374 - 1 Jul 2022
Cited by 3 | Viewed by 2564
Abstract
Extracellular vesicles (EVs) are considered as transporters of biomarkers for the diagnosis of cardiac diseases, playing an important role in cell-to-cell communication during physiological and pathological processes. However, specific markers for the isolation and analysis of cardiac EVs are missing, imposing limitation on [...] Read more.
Extracellular vesicles (EVs) are considered as transporters of biomarkers for the diagnosis of cardiac diseases, playing an important role in cell-to-cell communication during physiological and pathological processes. However, specific markers for the isolation and analysis of cardiac EVs are missing, imposing limitation on understanding their function in heart tissue. For this, we performed multiple proteomic approaches to compare EVs isolated from neonate rat cardiomyocytes and cardiac fibroblasts by ultracentrifugation, as well as EVs isolated from minced cardiac tissue and plasma by EVtrap. We identified Ldb3, a cytoskeletal protein which is essential in maintaining Z-disc structural integrity, as enriched in cardiac EVs. This result was validated using different EV isolation techniques showing Ldb3 in both large and small EVs. In parallel, we showed that Ldb3 is almost exclusively detected in the neonate rat heart when compared to other tissues, and specifically in cardiomyocytes compared to cardiac fibroblasts. Furthermore, Ldb3 levels, specifically higher molecular weight isoforms, were decreased in the left ventricle of ischemic heart failure patients compared to control groups, but not in the corresponding EVs. Our results suggest that Ldb3 could be a potential cardiomyocytes derived-EV marker and could be useful to identify cardiac EVs in physiological and pathological conditions. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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19 pages, 2669 KiB  
Article
Bone Marrow MSC Secretome Increases Equine Articular Chondrocyte Collagen Accumulation and Their Migratory Capacities
by Romain Contentin, Manon Jammes, Bastien Bourdon, Frédéric Cassé, Arnaud Bianchi, Fabrice Audigié, Thomas Branly, Émilie Velot and Philippe Galéra
Int. J. Mol. Sci. 2022, 23(10), 5795; https://doi.org/10.3390/ijms23105795 - 21 May 2022
Cited by 14 | Viewed by 3455
Abstract
Equine osteoarthritis (OA) leads to cartilage degradation with impaired animal well-being, premature cessation of sport activity, and financial losses. Mesenchymal stem cell (MSC)-based therapies are promising for cartilage repair, but face limitations inherent to the cell itself. Soluble mediators and extracellular vesicles (EVs) [...] Read more.
Equine osteoarthritis (OA) leads to cartilage degradation with impaired animal well-being, premature cessation of sport activity, and financial losses. Mesenchymal stem cell (MSC)-based therapies are promising for cartilage repair, but face limitations inherent to the cell itself. Soluble mediators and extracellular vesicles (EVs) secreted by MSCs are the alternatives to overcome those limitations while preserving MSC restorative properties. The effect of equine bone marrow MSC secretome on equine articular chondrocytes (eACs) was analyzed with indirect co-culture and/or MSC-conditioned media (CM). The expression of healthy cartilage/OA and proliferation markers was evaluated in eACs (monolayers or organoids). In vitro repair experiments with MSC-CM were made to evaluate the proliferation and migration of eACs. The presence of nanosized EVs in MSC-CM was appraised with nanoparticle tracking assay and transmission electron microscopy. Our results demonstrated that the MSC secretome influences eAC phenotype by increasing cartilage functionality markers and cell migration in a greater way than MSCs, which could delay OA final outcomes. This study makes acellular therapy an appealing strategy to improve equine OA treatments. However, the MSC secretome contains a wide variety of soluble mediators and small EVs, such as exosomes, and further investigation must be performed to understand the mechanisms occurring behind these promising effects. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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27 pages, 5348 KiB  
Article
The Role of Plasma Extracellular Vesicles in Remote Ischemic Conditioning and Exercise-Induced Ischemic Tolerance
by Tingting Gu, Jesper Just, Katrine Tang Stenz, Yan Yan, Peter Sieljacks, Jakob Wang, Thomas Skjaerlund Groennebaek, Jesper Emil Jakobsgaard, Emil Rindom, Jon Herskind, Anders Gravholt, Thomas Ravn Lassen, Mathias Jørgensen, Rikke Bæk, Eugenio Gutiérrez-Jiménez, Nina Kerting Iversen, Peter Mondrup Rasmussen, Jens Randel Nyengaard, Malene Møller Jørgensen, Frank de Paoli, Hans Erik Bøtker, Jørgen Kjems, Kristian Vissing and Kim Ryun Drasbekadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(6), 3334; https://doi.org/10.3390/ijms23063334 - 19 Mar 2022
Cited by 13 | Viewed by 4888
Abstract
Ischemic conditioning and exercise have been suggested for protecting against brain ischemia-reperfusion injury. However, the endogenous protective mechanisms stimulated by these interventions remain unclear. Here, in a comprehensive translational study, we investigated the protective role of extracellular vesicles (EVs) released after remote ischemic [...] Read more.
Ischemic conditioning and exercise have been suggested for protecting against brain ischemia-reperfusion injury. However, the endogenous protective mechanisms stimulated by these interventions remain unclear. Here, in a comprehensive translational study, we investigated the protective role of extracellular vesicles (EVs) released after remote ischemic conditioning (RIC), blood flow restricted resistance exercise (BFRRE), or high-load resistance exercise (HLRE). Blood samples were collected from human participants before and at serial time points after intervention. RIC and BFRRE plasma EVs released early after stimulation improved viability of endothelial cells subjected to oxygen-glucose deprivation. Furthermore, post-RIC EVs accumulated in the ischemic area of a stroke mouse model, and a mean decrease in infarct volume was observed for post-RIC EVs, although not reaching statistical significance. Thus, circulating EVs induced by RIC and BFRRE can mediate protection, but the in vivo and translational effects of conditioned EVs require further experimental verification. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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Review

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16 pages, 2888 KiB  
Review
Mitochondrial-Derived Vesicles—Link to Extracellular Vesicles and Implications in Cardiovascular Disease
by Jonas Heyn, Marina Augusto Heuschkel and Claudia Goettsch
Int. J. Mol. Sci. 2023, 24(3), 2637; https://doi.org/10.3390/ijms24032637 - 30 Jan 2023
Cited by 21 | Viewed by 7540
Abstract
Mitochondria are dynamic organelles regulating metabolism, cell death, and energy production. Therefore, maintaining mitochondrial health is critical for cellular homeostasis. Mitophagy and mitochondrial reorganization via fission and fusion are established mechanisms for ensuring mitochondrial quality. In recent years, mitochondrial-derived vesicles (MDVs) have emerged [...] Read more.
Mitochondria are dynamic organelles regulating metabolism, cell death, and energy production. Therefore, maintaining mitochondrial health is critical for cellular homeostasis. Mitophagy and mitochondrial reorganization via fission and fusion are established mechanisms for ensuring mitochondrial quality. In recent years, mitochondrial-derived vesicles (MDVs) have emerged as a novel cellular response. MDVs are shed from the mitochondrial surface and can be directed to lysosomes or peroxisomes for intracellular degradation. MDVs may contribute to cardiovascular disease (CVD) which is characterized by mitochondrial dysfunction. In addition, evidence suggests that mitochondrial content is present in extracellular vesicles (EVs). Herein, we provide an overview of the current knowledge on MDV formation and trafficking. Moreover, we review recent findings linking MDV and EV biogenesis and discuss their role in CVD. Finally, we discuss the role of vesicle-mediated mitochondrial transfer and its potential cardioprotective effects. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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27 pages, 1912 KiB  
Review
Extracellular Vesicles as Therapeutic Resources in the Clinical Environment
by Jorge Sanz-Ros, Cristina Mas-Bargues, Nekane Romero-García, Javier Huete-Acevedo, Mar Dromant and Consuelo Borrás
Int. J. Mol. Sci. 2023, 24(3), 2344; https://doi.org/10.3390/ijms24032344 - 25 Jan 2023
Cited by 30 | Viewed by 4140
Abstract
The native role of extracellular vesicles (EVs) in mediating the transfer of biomolecules between cells has raised the possibility to use them as therapeutic vehicles. The development of therapies based on EVs is now expanding rapidly; here we will describe the current knowledge [...] Read more.
The native role of extracellular vesicles (EVs) in mediating the transfer of biomolecules between cells has raised the possibility to use them as therapeutic vehicles. The development of therapies based on EVs is now expanding rapidly; here we will describe the current knowledge on different key points regarding the use of EVs in a clinical setting. These points are related to cell sources of EVs, isolation, storage, and delivery methods, as well as modifications to the releasing cells for improved production of EVs. Finally, we will depict the application of EVs therapies in clinical trials, considering the impact of the COVID-19 pandemic on the development of these therapies, pointing out that although it is a promising therapy for human diseases, we are still in the initial phase of its application to patients. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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32 pages, 1751 KiB  
Review
Extracellular Vesicles’ Role in the Pathophysiology and as Biomarkers in Cystic Fibrosis and COPD
by Sante Di Gioia, Valeria Daniello and Massimo Conese
Int. J. Mol. Sci. 2023, 24(1), 228; https://doi.org/10.3390/ijms24010228 - 23 Dec 2022
Cited by 6 | Viewed by 3639
Abstract
In keeping with the extraordinary interest and advancement of extracellular vesicles (EVs) in pathogenesis and diagnosis fields, we herein present an update to the knowledge about their role in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Although CF and COPD stem [...] Read more.
In keeping with the extraordinary interest and advancement of extracellular vesicles (EVs) in pathogenesis and diagnosis fields, we herein present an update to the knowledge about their role in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Although CF and COPD stem from a different origin, one genetic and the other acquired, they share a similar pathophysiology, being the CF transmembrane conductance regulator (CFTR) protein implied in both disorders. Various subsets of EVs, comprised mainly of microvesicles (MVs) and exosomes (EXOs), are secreted by various cell types that are either resident or attracted in the airways during the onset and progression of CF and COPD lung disease, representing a vehicle for metabolites, proteins and RNAs (especially microRNAs), that in turn lead to events as such neutrophil influx, the overwhelming of proteases (elastase, metalloproteases), oxidative stress, myofibroblast activation and collagen deposition. Eventually, all of these pathomechanisms lead to chronic inflammation, mucus overproduction, remodeling of the airways, and fibrosis, thus operating a complex interplay among cells and tissues. The detection of MVs and EXOs in blood and biological fluids coming from the airways (bronchoalveolar lavage fluid and sputum) allows the consideration of EVs and their cargoes as promising biomarkers for CF and COPD, although clinical expectations have yet to be fulfilled. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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19 pages, 1054 KiB  
Review
Therapeutic Strategy of Mesenchymal-Stem-Cell-Derived Extracellular Vesicles as Regenerative Medicine
by Yasunari Matsuzaka and Ryu Yashiro
Int. J. Mol. Sci. 2022, 23(12), 6480; https://doi.org/10.3390/ijms23126480 - 9 Jun 2022
Cited by 44 | Viewed by 7205
Abstract
Extracellular vesicles (EVs) are lipid bilayer membrane particles that play critical roles in intracellular communication through EV-encapsulated informative content, including proteins, lipids, and nucleic acids. Mesenchymal stem cells (MSCs) are pluripotent stem cells with self-renewal ability derived from bone marrow, fat, umbilical cord, [...] Read more.
Extracellular vesicles (EVs) are lipid bilayer membrane particles that play critical roles in intracellular communication through EV-encapsulated informative content, including proteins, lipids, and nucleic acids. Mesenchymal stem cells (MSCs) are pluripotent stem cells with self-renewal ability derived from bone marrow, fat, umbilical cord, menstruation blood, pulp, etc., which they use to induce tissue regeneration by their direct recruitment into injured tissues, including the heart, liver, lung, kidney, etc., or secreting factors, such as vascular endothelial growth factor or insulin-like growth factor. Recently, MSC-derived EVs have been shown to have regenerative effects against various diseases, partially due to the post-transcriptional regulation of target genes by miRNAs. Furthermore, EVs have garnered attention as novel drug delivery systems, because they can specially encapsulate various target molecules. In this review, we summarize the regenerative effects and molecular mechanisms of MSC-derived EVs. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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22 pages, 1610 KiB  
Review
Emerging Advances of Detection Strategies for Tumor-Derived Exosomes
by Huijuan Cheng, Qian Yang, Rongrong Wang, Ruhua Luo, Shanshan Zhu, Minhui Li, Wenqi Li, Cheng Chen, Yuqing Zou, Zhihua Huang, Tian Xie, Shuling Wang, Honghua Zhang and Qingchang Tian
Int. J. Mol. Sci. 2022, 23(2), 868; https://doi.org/10.3390/ijms23020868 - 14 Jan 2022
Cited by 21 | Viewed by 4454
Abstract
Exosomes derived from tumor cells contain various molecular components, such as proteins, RNA, DNA, lipids, and carbohydrates. These components play a crucial role in all stages of tumorigenesis and development. Moreover, they reflect the physiological and pathological status of parental tumor cells. Recently, [...] Read more.
Exosomes derived from tumor cells contain various molecular components, such as proteins, RNA, DNA, lipids, and carbohydrates. These components play a crucial role in all stages of tumorigenesis and development. Moreover, they reflect the physiological and pathological status of parental tumor cells. Recently, tumor-derived exosomes have become popular biomarkers for non-invasive liquid biopsy and the diagnosis of numerous cancers. The interdisciplinary significance of exosomes research has also attracted growing enthusiasm. However, the intrinsic nature of tumor-derived exosomes requires advanced methods to detect and evaluate the complex biofluid. This review analyzes the relationship between exosomes and tumors. It also summarizes the exosomal biological origin, composition, and application of molecular markers in clinical cancer diagnosis. Remarkably, this paper constitutes a comprehensive summary of the innovative research on numerous detection strategies for tumor-derived exosomes with the intent of providing a theoretical basis and reference for early diagnosis and clinical treatment of cancer. Full article
(This article belongs to the Special Issue Is Vesicular Therapy the Newcomer That Matters for the Medicine of Tomorrow?)
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