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The Molecular Basis of Extracellular Vesicles in Health and Diseases—2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 May 2026 | Viewed by 6871

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Dr. Taral R. Lunavat

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Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
Interests: extracellular vesicles; neuro-oncology; tumor immunology; tumor microenvironment; microRNAs; gene and cell therapy
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Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs), i.e., nanoparticles with a bilayer membrane, are secreted by almost all cell types and can be found in bodily fluids. EVs are heterogeneous and play a crucial role in cell-to-cell communication by carrying bioactive molecules that can modulate the behavior of target cells at both close and distant sites. The composition of EVs is determined by their biogenetic molecular pathway, as well as the microenvironment of the parent cell. Regardless of their origin, EVs carry a diverse set of bioactive molecules, including lipids, nucleic acids, and proteins, either inside the vesicle or exposed on their surface. Recent studies have provided valuable insight into the physiological and pathological roles of EVs. Technological advances in the detection, isolation, and characterization of EVs are significantly expanding, supporting research on their potential role in the diagnosis and therapy of various diseases, such as cancer, cardiovascular disease, autoimmune disorders, neurological diseases, and infectious diseases.

This Special Issue aims to provide comprehensive and critical knowledge on the pre-clinical and clinical applications of EVs in relation to the pathophysiology of different diseases, evaluate their diagnostic and therapeutic potential, and review the progress in this field. The published research articles will also provide new insights into the genetic and epigenetic predictors driven by EVs involved in the etiology of multiple diseases.

Scope and information for Authors:

This Special Issue covers various areas of research on the involvement of EVs in diseases, including genetics, epigenetics, RNAs, proteomics, metabolomics, and microbiome studies. The scope ranges from the most basic to the most clinically applied research, incorporating methodology, applications, and implications. We welcome submissions of research articles on the following sub-themes: extracellular vesicles and circulating nucleic acids, extracellular vesicles for the transport of genetic information and gene therapy, the transfer of nucleic acid to mediate communication by extracellular vesicles, the role of extracellular vesicles in epigenetics, microbiota-derived extracellular vesicles and their molecular cargo, extracellular vesicles as biomarkers and therapeutic targets, the heterogeneity of EVs in diseases, and new technology to isolate and characterize EVs.

The Special Issue is open access and both reviews and original research articles are welcome for submissions.

Dr. Taral R. Lunavat
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

exosomes
microvesicles
extracellular vesicles
genetic material
therapeutics
diagnostics
biomarkers
molecular pathway
liquid biopsy
metabolism
omics

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The Molecular Basis of Extracellular Vesicles in Health and Diseases in International Journal of Molecular Sciences (15 articles)

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Research

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33 pages, 10033 KB

Open AccessArticle

Mesenchymal Stem Cell-Derived Exosomes Reprogram Chemosensitivity Pathways in Cervical Cancer Spheroids

by Piyatida Molika, Kesara Nittayaboon, Kankamol Kerdkumthong and Raphatphorn Navakanitworakul

Int. J. Mol. Sci. 2026, 27(3), 1575; https://doi.org/10.3390/ijms27031575 - 5 Feb 2026

Viewed by 681

Abstract

Cervical cancer (CC) remains a major global health challenge due to chemotherapy resistance and recurrence. Mesenchymal stem cell-derived exosomes (MSC-exosomes) have dual roles, as they can act as therapeutic agents and contribute to chemoresistance. However, their role in response to chemotherapy in CC remains unclear. Therefore, our study investigated the effects of MSC-exosome pretreatment on chemotherapy sensitivity using three-dimensional spheroid models generated from HeLa and SiHa CC cell lines. Proteomic profiling of MSC-exosomes identified key proteins, including ANXA1, ANXA2, EEF2, LGALS1, and PKM2, associated with tumor regeneration and chemotherapy response. MSC-exosomes exhibited context-dependent effects in both chemoresistance and chemosensitization by modulating drug efflux, metabolic reprogramming, stress adaptation, apoptosis, DNA damage response, and integrin-mediated signaling. MSC-exosome pretreatment altered spheroid responses to paclitaxel in combination with cisplatin or carboplatin. MSC-exosomes significantly enhanced chemotherapy-induced cytotoxicity in HeLa spheroids, as evidenced by reduced cell viability, increased caspase activity, and upregulation of the pro-apoptotic marker Bax. In contrast, SiHa spheroids represented selective responses: MSC-exosome pretreatment did not enhance sensitivity to paclitaxel–cisplatin but improved responsiveness to paclitaxel–carboplatin, particularly within the spheroid core. Overall, MSC-exosome pretreatment exerts cell type and drug-specific effects in CC spheroids, supporting their potential to modulate chemotherapy response. Full article

(This article belongs to the Special Issue The Molecular Basis of Extracellular Vesicles in Health and Diseases—2nd Edition)

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17 pages, 2839 KB

Open AccessArticle

Optimizing Small RNA Sequencing for Salivary Biomarker Identification: A Comparative Study of Library Preparation Protocols

by Ulrike Kegler, Nathalie Ropek, Manuela Hofner, Silvia Schönthaler, Klemens Vierlinger and Christa Nöhammer

Int. J. Mol. Sci. 2025, 26(23), 11437; https://doi.org/10.3390/ijms262311437 - 26 Nov 2025

Viewed by 1172

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and hold significant potential as biomarkers. Saliva, a non-invasive and easily accessible biofluid, offers a promising alternative to blood for miRNA-based diagnostics. However, miRNA profiling by next-generation sequencing (NGS) is highly influenced by library preparation protocol, which can introduce detection and quantification biases. This study compared four commercial small RNA library preparation kits—QIASeq miRNA library kit (Qiagen), RealSeq-Biofluids Plasma/Serum miRNA library kit (Somagenics), Small RNA-seq library prep kit (Lexogen) and NEBNext multiplex small RNA library prep set for illumina (set 1) (New England BioLabs)—to evaluate their performance in profiling miRNAs from cell-free saliva, plasma and their extracellular vesicles (EVs). Using both synthetic reference and biological samples, we assessed the kits’ efficiency in handling low RNA input, minimizing bias and detecting diverse miRNAs. QIAseq outperformed the others, showing the highest miRNA mapping rates, minimal adapter dimers and the broadest miRNA detection, particularly in saliva. Moreover, substantial overlap between saliva- and plasma-derived miRNAs supports saliva’s diagnostic potential. Overall, this study underscores the critical impact of library preparation on miRNA sequencing outcomes and offers guidance for selecting optimal protocols for biomarker discovery from non-invasive sample matrices. Full article

(This article belongs to the Special Issue The Molecular Basis of Extracellular Vesicles in Health and Diseases—2nd Edition)

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20 pages, 4603 KB

Open AccessArticle

Transcriptomic Response to Neuromuscular Electrical Stimulation in Muscle, Brain, and Plasma EVs in WT and Klotho-Deficient Mice

by Catherine Anne Cavanaugh, Amanda E. Moore, Nicholas Francis Fitz, Iliya Lefterov and Radosveta Koldamova

Int. J. Mol. Sci. 2025, 26(16), 7849; https://doi.org/10.3390/ijms26167849 - 14 Aug 2025

Cited by 1 | Viewed by 1331

Abstract

Neuromuscular electrical stimulation (NMES) has been shown to improve motor activities and daily living. Prior studies indicated extracellular vesicles (EVs) play a role in cellular communication. Here, we evaluated transcriptomic profiles of tibialis muscle, brain, and plasma-derived EVs following NMES in wild type (WT) and Klotho heterozygous (Kl^HET) mice. Muscle RNA-seq data demonstrated that, in both genotypes, the most upregulated functional categories were related to glucose metabolism and response to insulin, with pathways uniquely affected in each genotype. There was a similarity of the non-coding RNA transcriptome of plasma EVs, with functional patterns suggesting response to oxygen and insulin and long-term synaptic potentiation. The brain transcriptome showed little functional overlap between WT and Kl^HET mice. In WT, brain upregulation of genes was related to blood flow and cell adhesion processes, while Kl^HET showed upregulation of immune function. The results indicate that similar metabolic function is impacted in the location of stimulation, but the distal impact of stimulation on the brain is associated with Klotho deficiency. Full article

(This article belongs to the Special Issue The Molecular Basis of Extracellular Vesicles in Health and Diseases—2nd Edition)

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23 pages, 3871 KB

Open AccessArticle

Proteomics of Bacterial and Mouse Extracellular Vesicles Released in the Gastrointestinal Tracts of Nutrient-Stressed Animals Reveals an Interplay Between Microbial Serine Proteases and Mammalian Serine Protease Inhibitors

by Régis Stentz, Emily Jones, Lejla Gul, Dimitrios Latousakis, Aimee Parker, Arlaine Brion, Andrew J. Goldson, Kathryn Gotts and Simon R. Carding

Int. J. Mol. Sci. 2025, 26(9), 4080; https://doi.org/10.3390/ijms26094080 - 25 Apr 2025

Cited by 1 | Viewed by 2296

Abstract

Bacterial extracellular vesicles (BEVs) produced by members of the intestinal microbiota can not only contribute to digestion but also mediate microbe–host cell communication via the transfer of functional biomolecules to mammalian host cells. An unresolved question is which host factors and conditions influence BEV cargo and how they impact host cell function. To address this question, we analysed and compared the proteomes of BEVs released by the major human gastrointestinal tract (GIT) symbiont Bacteroides thetaiotaomicron (Bt) in vivo in fed versus fasted animals using nano-liquid chromatography with tandem mass spectrometry (LC-MSMS). Among the proteins whose abundance was negatively affected by fasting, nine of ten proteins of the serine protease family, including the regulatory protein dipeptidyl peptidase-4 (DPP-4), were significantly decreased in BEVs produced in the GITs of fasted animals. Strikingly, in extracellular vesicles produced by the intestinal epithelia of the same fasted mice, the proteins with the most increased abundance were serine protease inhibitors (serpins). Together, these findings suggest a dynamic interaction between GI bacteria and the host. Additionally, they indicate a regulatory role for the host in determining the balance between bacterial serine proteases and host serpins exported in bacterial and host extracellular vesicles. Full article

(This article belongs to the Special Issue The Molecular Basis of Extracellular Vesicles in Health and Diseases—2nd Edition)

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26 pages, 1099 KB

Open AccessReview

Connecting the Dots: Milestones in the History of Extracellular Vesicle Research

by Joanna Guzowska, Szymon Kowalski, Iga Schachta, Natalia Piekuś-Słomka and Artur Słomka

Int. J. Mol. Sci. 2026, 27(5), 2470; https://doi.org/10.3390/ijms27052470 - 7 Mar 2026

Cited by 1 | Viewed by 690

Abstract

The field of extracellular vesicle (EV) research offers a compelling example of a biological concept refined through continuous methodological innovation. This review traces the historical trajectory of the discipline chronologically, beginning with early observations in haemostasis, from Malpighi’s descriptions of blood clots and Chargaff and West’s identification of a procoagulant sedimentable plasma fraction, to Wolf’s “platelet dust,” Crawford’s microparticles characterised by electron microscopy, and the seminal work by Stahl and Johnstone demonstrating regulated vesicle biogenesis during reticulocyte maturation via multivesicular bodies. We highlight a pivotal conceptual shift, from viewing EVs as cellular debris to recognising them as regulated “communicasomes,” catalysed by Raposo’s discovery of antigen-presenting exosomes and subsequent evidence for EV-mediated transfer of functional receptors and nucleic acids, including the influential and sometimes debated model proposed by Ratajczak. By integrating findings from matrix vesicles, plant-derived vesicles, and diverse tissue contexts, we frame EV release as an evolutionarily conserved process with profound implications for immunity, regeneration, oncology, and cardiovascular pathology. A second central aim of this review is practical and methodological. We map how the expansion of biological claims has driven urgent standardisation efforts, notably through the establishment of the International Society for Extracellular Vesicles (ISEV) and the successive MISEV guidelines (2014, 2018, 2023). These are complemented by community resources such as EV-TRACK, MIFlowCyt-EV, and the databases ExoCarta and Vesiclepedia. We summarise core experimental choices across isolation and characterisation techniques, including ultracentrifugation, size exclusion chromatography, density gradients, flow cytometry, nanoparticle tracking analysis, and electron microscopy, while outlining persistent bottlenecks in purity, standardised nomenclature, and experimental reproducibility. Finally, we provide concise biographical sketches of key contributors and an overview of major EV-focused journals and ISEV meetings that anchor consensus-building and the translation of fundamental knowledge into clinical and industrial applications. Full article

(This article belongs to the Special Issue The Molecular Basis of Extracellular Vesicles in Health and Diseases—2nd Edition)

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