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Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications
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Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications

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

Deadline for manuscript submissions: 20 October 2025 | Viewed by 5618

Special Issue Editor

Prof. Dr. Jung-Hyun Lee

E-Mail Website
Guest Editor
Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
Interests: viurs infection; extracellular vesicles; virus-host interactions; immune responses; immune sensors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) have emerged as critical players in intercellular communication, serving as vehicles for the transfer of proteins, lipids, nucleic acids, and metabolites between cells. These membrane-bound structures, ranging from 30 to 5000 nm, are released by both eukaryotic and prokaryotic cells under normal physiological conditions as well as during disease states. Their roles are rapidly being recognized in a wide array of biological processes, including immune modulation, cellular homeostasis, and tissue regeneration, as well as in the progression of pathological conditions such as cancer, neurodegenerative disorders, cardiovascular diseases, autoimmunity, and infectious diseases.

In recent years, the field of EV research has rapidly advanced, uncovering novel insights into how these vesicles contribute to disease pathology, serve as biomarkers, and even act as potential therapeutic targets and delivery systems. These discoveries highlight the tremendous potential of EVs to revolutionize diagnostics and treatment strategies across various medical fields.

This Special Issue aims to provide a platform for cutting-edge research and comprehensive reviews that explore the multifaceted roles of extracellular vesicles in health and disease.

We welcome both original research and review articles that offer novel perspectives on the impact of EVs across different physiological and pathological landscapes.

Prof. Dr. Jung-Hyun Lee
Guest Editor

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Keywords

  • extracellular vesicles
  • intercellular communications
  • biomarkers
  • drug delivery systems

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Published Papers (6 papers)

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Research

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15 pages, 3414 KiB  
Article
Extracellular Competing Endogenous RNA Networks Reveal Key Regulators of Early Amyloid Pathology Propagation in Alzheimer’s Disease
by Misael Leonardo López-Cepeda, Andrea Angarita-Rodríguez, Alexis Felipe Rojas-Cruz, Julián Pérez Mejia, Robin Khatri, Michael Brehler, Eduardo Martínez-Martínez, Andrés Pinzón, Andrés Felipe Aristizabal-Pachon and Janneth González
Int. J. Mol. Sci. 2025, 26(8), 3544; https://doi.org/10.3390/ijms26083544 - 9 Apr 2025
Viewed by 374
Abstract
Extracellular vesicles (EVs) are small capsular bodies released by cells, mediating responses in intercellular communication. The role of EVs in Aβ pathology spreading in the Alzheimer’s disease (AD) brain has been evidenced, although whether this occurs due to the co-transportation of Aβ peptides [...] Read more.
Extracellular vesicles (EVs) are small capsular bodies released by cells, mediating responses in intercellular communication. The role of EVs in Aβ pathology spreading in the Alzheimer’s disease (AD) brain has been evidenced, although whether this occurs due to the co-transportation of Aβ peptides or contribution of other factors, such as EV-associated transcripts, remains uncertain. In vitro studies of miRNA cargo in neuron-derived extracellular vesicles (NDEVs) show that Aβ hyperexpression alters the transcriptomic profile; however, it is not clear to what extent this causes changes at the organ level. By utilizing datasets from published studies, we generated competing endogenous RNA (ceRNA) networks for miRNAs co-expressed in NDEVs and the brain in different stages of pathology, using both an APP overexpressing neuronal model (in vitro) and brain cortices from 6- and 9-month-old APP/PSEN1 mice (in vivo). Networks integrating information from mRNAs, lncRNAs, and circRNAs showed two candidate lncRNAs (Kcnq1ot1 and Gm42969) and a circRNA (Pum1), while enrichment analyses detected that NDEVs miRNAs signal to other CNS cells and that this signal can be disrupted by Aβ pathology, contributing to the loss of long-term potentiation seen in early AD. Full article
(This article belongs to the Special Issue Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications)
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22 pages, 4702 KiB  
Article
Engineered ATP-Loaded Extracellular Vesicles Derived from Mesenchymal Stromal Cells: A Novel Strategy to Counteract Cell ATP Depletion in an In Vitro Model
by Maria Antonietta Grignano, Silvia Pisani, Marilena Gregorini, Giorgia Rainaudo, Maria Antonietta Avanzini, Stefania Croce, Chiara Valsecchi, Gabriele Ceccarelli, Tefik Islami, Elisabetta Margiotta, Valentina Portalupi, Andreana De Mauri, Emma Diletta Stea, Eleonora Francesca Pattonieri, Paolo Iadarola, Simona Viglio, Bice Conti and Teresa Rampino
Int. J. Mol. Sci. 2025, 26(7), 3424; https://doi.org/10.3390/ijms26073424 - 5 Apr 2025
Viewed by 528
Abstract
The use of adenosine triphosphate (ATP) has shown promising effects in alleviating ischemic damage across various tissues. However, the penetration of ATP into kidney tubular cells presents a challenge due to their unique anatomical and physiological properties. In this study, we introduce a [...] Read more.
The use of adenosine triphosphate (ATP) has shown promising effects in alleviating ischemic damage across various tissues. However, the penetration of ATP into kidney tubular cells presents a challenge due to their unique anatomical and physiological properties. In this study, we introduce a novel bioinspired drug delivery system utilizing extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) and engineered to carry ATP. ATP-loaded liposomes (ATP-LPs) and ATP-loaded EVs (ATP-EVs) were prepared using microfluidic technology, followed by characterization of their morphology (DLS, NTA, SEM, TEM), ATP content, and release rate at 37 °C (pH 7.4). Additionally, the delivery efficacy of ATP-LPs and ATP-EVs was evaluated in vitro on renal cells (HK2 cells) under chemically induced ischemia. The results indicated successful ATP enrichment in EVs, with ATP-EVs showing no significant changes in morphology or size compared to naïve EVs. Notably, ATP-EVs demonstrated superior ATP retention compared to ATP-LPs, protecting the ATP from degradation in the extracellular environment. In an ATP-depleted HK2 cell model, only ATP-EVs effectively restored ATP levels, preserving cell viability and reducing apoptotic gene expression (BCL2-BAX). This study is the first to successfully demonstrate the direct delivery of ATP into renal tubular cells in vitro using EVs as carriers. Full article
(This article belongs to the Special Issue Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications)
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14 pages, 1422 KiB  
Article
Extracellular Vesicles Analysis as Possible Signatures of Antiphospholipid Syndrome Clinical Features
by Giulio Luigi Bonisoli, Giuseppe Argentino, Simonetta Friso and Elisa Tinazzi
Int. J. Mol. Sci. 2025, 26(7), 2834; https://doi.org/10.3390/ijms26072834 - 21 Mar 2025
Viewed by 340
Abstract
Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by thrombosis and obstetric complications. Extracellular vesicles (EVs) of either platelet and endothelial origin are recognized to be involved in the pathophysiology of the disease. This study aimed to evaluate the potential role of [...] Read more.
Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by thrombosis and obstetric complications. Extracellular vesicles (EVs) of either platelet and endothelial origin are recognized to be involved in the pathophysiology of the disease. This study aimed to evaluate the potential role of endothelial- and platelet-derived extracellular vesicles and the clinical features or progression of APS. We enrolled 22 patients diagnosed with APS and 18 age and sex-matched healthy controls. We determined APS-specific antibody positivity and clinical manifestations in APS affected patients, with a focus on neurological, cardiovascular, dermatological, hematological manifestations, and pregnancy-related complications. Platelet-poor plasma was collected from either patients and controls for the analysis of EVs by flow cytometry technology using monoclonal antibodies to specifically identify those derived from either platelets and/or endothelial cells. EVs of endothelial and platelet origins were overall significantly increased in patients as compared to healthy controls. Furthermore, a significant association was also observed between the number of extracellular vesicles and specific organ involvement, particularly central nervous system manifestations, hematological abnormalities, and obstetric complications. An elevated proportion of endothelial-derived EVs in APS and a reduction of resting endothelial cell-derived EVs were observed in APS-affected women with obstetric complications. Our findings highlight the involvement of endothelial cells and platelets in mirroring the activities of endothelial cells and platelets in APS. Additionally, extracellular vesicles may serve as potential predictors of organ involvement and disease-related damage. Full article
(This article belongs to the Special Issue Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications)
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20 pages, 10073 KiB  
Article
Role of Glycans in Equine Endometrial Cell Uptake of Extracellular Vesicles Derived from Amniotic Mesenchymal Stromal Cells
by Giulia Gaspari, Anna Lange-Consiglio, Fausto Cremonesi and Salvatore Desantis
Int. J. Mol. Sci. 2025, 26(4), 1784; https://doi.org/10.3390/ijms26041784 - 19 Feb 2025
Viewed by 568
Abstract
Extracellular vesicles (EVs) are important mediators of cell–cell communication thanks to their ability to transfer their bioactive cargo, thus regulating a variety of physiological contexts. EVs derived from amniotic mesenchymal/stromal cells (eAMC-EVs) are internalized by equine endometrial cells (eECs) with positive effects on [...] Read more.
Extracellular vesicles (EVs) are important mediators of cell–cell communication thanks to their ability to transfer their bioactive cargo, thus regulating a variety of physiological contexts. EVs derived from amniotic mesenchymal/stromal cells (eAMC-EVs) are internalized by equine endometrial cells (eECs) with positive effects on regenerative medicine treatments. As the cellular uptake of EVs is influenced by the glycan profile of both EVs and target cells, this study is focused on the role of surface glycans in the uptake of eAMC-EVs by recipient eECs. Equine ECs were obtained by enzymatic digestion of uteri from healthy mares. Equine AMC-EVs were isolated from amniotic cell cultures according to a standardized protocol. The glycan pattern was studied using a panel of lectins in combination with fucosidase and neuraminidase treatment. Both eECs and eAMC-EVs expressed N-linked high mannose glycans, as well as fucosylated and sialylated glycans. All these glycans were involved in the uptake of eAMC-EVs by eECs. The internalization of eAMC-EVs was strongly reduced after cleavage of α1,2-linked fucose and α2,3/α2,6-linked sialic acids. These results demonstrate that surface glycans are involved in the internalization of eAMC-EVs by eECs and that fucosylated and sialylated glycans are highly relevant in the transfer of bioactive molecules with effects on regenerative medicine treatments. Full article
(This article belongs to the Special Issue Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications)
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Review

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27 pages, 999 KiB  
Review
Stem Cell-Derived Extracellular Vesicle-Mediated Therapeutic Signaling in Spinal Cord Injury
by Raju Poongodi, Yung-Wei Hsu, Tao-Hsiang Yang, Ya-Hsien Huang, Kuender D. Yang, Hsin-Chieh Lin and Jen-Kun Cheng
Int. J. Mol. Sci. 2025, 26(2), 723; https://doi.org/10.3390/ijms26020723 - 16 Jan 2025
Cited by 1 | Viewed by 1266
Abstract
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic strategy for spinal cord injury (SCI). These nanosized vesicles possess unique properties such as low immunogenicity and the ability to cross biological barriers, making them ideal carriers for delivering bioactive molecules [...] Read more.
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic strategy for spinal cord injury (SCI). These nanosized vesicles possess unique properties such as low immunogenicity and the ability to cross biological barriers, making them ideal carriers for delivering bioactive molecules to injured tissues. MSC-EVs have been demonstrated to exert multiple beneficial effects in SCI, including reducing inflammation, promoting neuroprotection, and enhancing axonal regeneration. Recent studies have delved into the molecular mechanisms underlying MSC-EV-mediated therapeutic effects. Exosomal microRNAs (miRNAs) have been identified as key regulators of various cellular processes involved in SCI pathogenesis and repair. These miRNAs can influence inflammation, oxidative stress, and apoptosis by modulating gene expression. This review summarized the current state of MSC-EV-based therapies for SCI, highlighting the underlying mechanisms and potential clinical applications. We discussed the challenges and limitations of translating these therapies into clinical practice, such as inconsistent EV production, complex cargo composition, and the need for targeted delivery strategies. Future research should focus on optimizing EV production and characterization, identifying key therapeutic miRNAs, and developing innovative delivery systems to maximize the therapeutic potential of MSC-EVs in SCI. Full article
(This article belongs to the Special Issue Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications)
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23 pages, 1331 KiB  
Review
Adipose Tissue as a Major Launch Spot for Circulating Extracellular Vesicle-Carried MicroRNAs Coordinating Tissue and Systemic Metabolism
by Paula Diez-Roda, Elena Perez-Navarro and Ruben Garcia-Martin
Int. J. Mol. Sci. 2024, 25(24), 13488; https://doi.org/10.3390/ijms252413488 - 17 Dec 2024
Viewed by 1544
Abstract
Circulating microRNAs (miRNAs), especially transported by extracellular vesicles (EVs), have recently emerged as major new participants in interorgan communication, playing an important role in the metabolic coordination of our tissues. Among these, adipose tissue displays an extraordinary ability to secrete a vast list [...] Read more.
Circulating microRNAs (miRNAs), especially transported by extracellular vesicles (EVs), have recently emerged as major new participants in interorgan communication, playing an important role in the metabolic coordination of our tissues. Among these, adipose tissue displays an extraordinary ability to secrete a vast list of EV-carried miRNAs into the circulation, representing new hormone-like factors. Despite the limitations of current methodologies for the unequivocal identification of the origin and destination of EV-carried miRNAs in vivo, recent investigations clearly support the important regulatory role of adipose-derived circulating miRNAs in shaping the metabolism and function of other tissues including the liver, muscle, endocrine pancreas, cardiovascular system, gastrointestinal tract, and brain. Here, we review the most recent findings regarding miRNAs transported by adipose-derived EVs (AdEVs) targeting other major metabolic organs and the implications of this dialog for physiology and pathology. We also review here the current and potential future diagnostic and therapeutic applications of AdEV-carried miRNAs. Full article
(This article belongs to the Special Issue Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications)
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