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Exosomes and Non-Coding RNA Research in Health and Disease

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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: 11 June 2025 | Viewed by 29966

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Prof. Dr. Stergios Boussios

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1. Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King’s College London, London SE1 9RT, UK
2. Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, Kent, UK
3. Kent Medway Medical School, University of Kent, Canterbury CT2 7LX, Kent, UK
4. AELIA Organization, 9(th)Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
Interests: prostate cancer; renal cancer; ovarian cancer; homologous recombination of DNA; PARP inhibitors; cervical cancer; carcinoma of unknown primary; colorectal cancer; cancer and autoimmune diseases; biomarkers
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Dear Colleague,

The Special Issue on "Exosomes and Non-coding RNA Research in Health and Disease" explores the significant advancements in understanding the roles of exosomes and non-coding RNA in various physiological and pathological processes. This collection of research articles sheds light on the intricate interplay between exosomes and non-coding RNA and their impact on health and disease.

The studies featured in this Special Issue highlight the diverse functions of exosomes, including their involvement in intercellular communication, immune regulation, and disease progression. Additionally, the role of non-coding RNA, such as microRNAs, long non-coding RNAs, and circular RNAs, in gene expression regulation and cellular processes is extensively discussed.

The research presented in this Special Issue covers a wide range of diseases, including cancer, neurodegenerative disorders, cardiovascular diseases, and immune-related disorders. It provides valuable insights into the diagnostic, prognostic, and therapeutic potential of exosomes and non-coding RNA in these diseases.

Overall, this Special Issue serves as a comprehensive resource for researchers and clinicians interested in the emerging field of exosomes and non-coding RNA. The findings presented here contribute to our understanding of the complex mechanisms underlying health and disease, paving the way for the development of novel diagnostic tools and therapeutic strategies.

Dr. Stergios Boussios
Guest Editor

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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 100 words) can be sent to the Editorial Office for announcement on this website.

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

exosomes
non-coding RNA
health
disease
intercellular communication
cancer
neurodegenerative disorders
cardiovascular diseases
immune regulation
therapeutic strategies

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Published Papers (11 papers)

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Research

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14 pages, 2693 KiB

Open AccessArticle

Machine Learning-Based Etiologic Subtyping of Ischemic Stroke Using Circulating Exosomal microRNAs

by Ji Hoon Bang, Eun Hee Kim, Hyung Jun Kim, Jong-Won Chung, Woo-Keun Seo, Gyeong-Moon Kim, Dong-Ho Lee, Heewon Kim and Oh Young Bang

Int. J. Mol. Sci. 2024, 25(12), 6761; https://doi.org/10.3390/ijms25126761 - 20 Jun 2024

Cited by 1 | Viewed by 1186

Abstract

Ischemic stroke is a major cause of mortality worldwide. Proper etiological subtyping of ischemic stroke is crucial for tailoring treatment strategies. This study explored the utility of circulating microRNAs encapsulated in extracellular vesicles (EV-miRNAs) to distinguish the following ischemic stroke subtypes: large artery atherosclerosis (LAA), cardioembolic stroke (CES), and small artery occlusion (SAO). Using next-generation sequencing (NGS) and machine-learning techniques, we identified differentially expressed miRNAs (DEMs) associated with each subtype. Through patient selection and diagnostic evaluation, a cohort of 70 patients with acute ischemic stroke was classified: 24 in the LAA group, 24 in the SAO group, and 22 in the CES group. Our findings revealed distinct EV-miRNA profiles among the groups, suggesting their potential as diagnostic markers. Machine-learning models, particularly logistic regression models, exhibited a high diagnostic accuracy of 92% for subtype discrimination. The collective influence of multiple miRNAs was more crucial than that of individual miRNAs. Additionally, bioinformatics analyses have elucidated the functional implications of DEMs in stroke pathophysiology, offering insights into the underlying mechanisms. Despite limitations like sample size constraints and retrospective design, our study underscores the promise of EV-miRNAs coupled with machine learning for ischemic stroke subtype classification. Further investigations are warranted to validate the clinical utility of the identified EV-miRNA biomarkers in stroke patients. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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13 pages, 314 KiB

Open AccessArticle

Changes in Circulating MicroRNA Levels as Potential Indicators of Training Adaptation in Professional Volleyball Players

by Dominika Podgórska, Marek Cieśla, Artur Płonka, Wojciech Bajorek, Wojciech Czarny, Paweł Król and Rafał Podgórski

Int. J. Mol. Sci. 2024, 25(11), 6107; https://doi.org/10.3390/ijms25116107 - 1 Jun 2024

Viewed by 691

Abstract

The increasing demand placed on professional athletes to enhance their fitness and performance has prompted the search for new, more sensitive biomarkers of physiological ability. One such potential biomarker includes microRNA (miRNA) small regulatory RNA sequences. The study investigated the levels of the selected circulating miRNAs before and after a 10-week training cycle in 12 professional female volleyball players, as well as their association with cortisol, creatine kinase (CK), and interleukin 6 (IL-6), using the qPCR technique. Significant decreases in the miR-22 (0.40 ± 0.1 vs. 0.28 ± 0.12, p = 0.009), miR-17 (0.35 ± 0.13 vs. 0.23 ± 0.08; p = 0.039), miR-24 (0.09 ± 0.04 vs. 0.05 ± 0.02; p = 0.001), and miR-26a (0.11 ± 0.06 vs. 0.06 ± 0.04; p = 0.003) levels were observed after training, alongside reduced levels of cortisol and IL-6. The correlation analysis revealed associations between the miRNAs’ relative quantity and the CK concentrations, highlighting their potential role in the muscle repair processes. The linear regression analysis indicated that miR-24 and miR-26a had the greatest impact on the CK levels. The study provides insights into the dynamic changes in the miRNA levels during training, suggesting their potential as biomarkers for monitoring the adaptive responses to exercise. Overall, the findings contribute to a better understanding of the physiological effects of exercise and the potential use of miRNAs, especially miR-24 and miR-26a, as biomarkers in sports science and medicine. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

12 pages, 8485 KiB

Open AccessArticle

RNA Profile of Cell Bodies and Exosomes Released by Tumorigenic and Non-Tumorigenic Thyroid Cells

by Valentina Maggisano, Francesca Capriglione, Catia Mio, Stefania Bulotta, Giuseppe Damante, Diego Russo and Marilena Celano

Int. J. Mol. Sci. 2024, 25(3), 1407; https://doi.org/10.3390/ijms25031407 - 24 Jan 2024

Viewed by 1517

Abstract

Tumor cells release exosomes, extracellular vesicle containing various bioactive molecules such as protein, DNA and RNA. The analysis of RNA molecules packaged in exosomes may provide new potential diagnostic or prognostic tumor biomarkers. The treatment of radioiodine-refractory aggressive thyroid cancer is still an unresolved clinical challenge, and the search for biomarkers that are detectable in early phase of the disease has become a fundamental goal for thyroid cancer research. By using transcriptome analysis, this study aimed to analyze the gene expression profiles of exosomes secreted by a non-tumorigenic thyroid cell line (Nthy-ori 3.1-exo) and a papillary thyroid cancer (TPC-1-exo) cell line, comparing them with those of cell bodies (Nthy-ori 3.1-cells and TPC-1-cells). A total of 9107 transcripts were identified as differentially expressed when comparing TPC-1-exo with TPC-1-cells and 5861 when comparing Nthy-ori 3.1-exo with Nthy-ori 3.1-cells. Among them, Sialic acid-binding immunoglobulin-like lectins 10 and 11 (SIGLEC10, SIGLEC11) and Keratin-associated protein 5 (KRTAP5-3) transcripts, genes known to be involved in cancer progression, turned out to be up-regulated only in TPC-1-exo. Gene ontology analysis revealed significantly enriched pathways, and only in TPC-1-exo were the differential expressed genes associated with an up-regulation in epigenetic processes. These findings provide a proof of concept that some mRNA species are specifically packaged in tumor-cell-derived exosomes and may constitute a starting point for the identification of new biomarkers for thyroid tumors. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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19 pages, 3055 KiB

Open AccessArticle

The Binding of Pseudomonas aeruginosa to Cystic Fibrosis Bronchial Epithelial Model Cells Alters the Composition of the Exosomes They Produce Compared to Healthy Control Cells

by Víctor Lozano-Iturbe, Noelia Blanco-Agudín, Emma Vázquez-Espinosa, Iván Fernández-Vega, Jesús Merayo-Lloves, Fernando Vazquez, Rosa M. Girón and Luis M. Quirós

Int. J. Mol. Sci. 2024, 25(2), 895; https://doi.org/10.3390/ijms25020895 - 11 Jan 2024

Cited by 1 | Viewed by 1469

Abstract

Cystic fibrosis (CF) is a genetic disease that causes dehydration of the surface of the airways, increasing lung infections, most frequently caused by Pseudomonas aeruginosa. Exosomes are nanovesicles released by cells that play an essential role in intercellular communication, although their role during bacterial infections is not well understood. In this article, we analyze the alterations in exosomes produced by healthy bronchial epithelial and cystic fibrosis cell lines caused by the interaction with P. aeruginosa. The proteomic study detected alterations in 30% of the species analyzed. In healthy cells, they mainly involve proteins related to the extracellular matrix, cytoskeleton, and various catabolic enzymes. In CF, proteins related to the cytoskeleton and matrix, in addition to the proteasome. These differences could be related to the inflammatory response. A study of miRNAs detected alterations in 18% of the species analyzed. The prediction of their potential biological targets identified 7149 genes, regulated by up to 7 different miRNAs. The identification of their functions showed that they preferentially affected molecules involved in binding and catalytic activities, although with differences between cell types. In conclusion, this study shows differences in exosomes between CF and healthy cells that could be involved in the response to infection. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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Review

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17 pages, 1428 KiB

Open AccessReview

Proteomic Analysis of Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review

by Illayaraja Krishnan, Alvin Man Lung Chan, Jia Xian Law, Min Hwei Ng, Jaime Jacqueline Jayapalan and Yogeswaran Lokanathan

Int. J. Mol. Sci. 2024, 25(10), 5340; https://doi.org/10.3390/ijms25105340 - 14 May 2024

Cited by 1 | Viewed by 1879

Abstract

Numerous challenges remain within conventional cell-based therapy despite the growing trend of stem cells used to treat various life-debilitating diseases. These limitations include batch-to-batch heterogeneity, induced alloreactivity, cell survival and integration, poor scalability, and high cost of treatment, thus hindering successful translation from lab to bedside. However, recent pioneering technology has enabled the isolation and enrichment of small extracellular vesicles (EVs), canonically known as exosomes. EVs are described as a membrane-enclosed cargo of functional biomolecules not limited to lipids, nucleic acid, and proteins. Interestingly, studies have correlated the biological role of MSC-EVs to the paracrine activity of MSCs. This key evidence has led to rigorous studies on MSC-EVs as an acellular alternative. Using EVs as a therapy was proposed as a model leading to improvements through increased safety; enhanced bioavailability due to size and permeability; reduced heterogeneity by selective and quantifiable properties; and prolonged shelf-life via long-term freezing or lyophilization. Yet, the identity and potency of EVs are still relatively unknown due to various methods of preparation and to qualify the final product. This is reflected by the absence of regulatory strategies overseeing manufacturing, quality control, clinical implementation, and product registration. In this review, the authors review the various production processes and the proteomic profile of MSC-EVs. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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23 pages, 4653 KiB

Open AccessReview

Human Vault RNAs: Exploring Their Potential Role in Cellular Metabolism

by Magdalena Taube, Natalia Lisiak, Ewa Totoń and Błażej Rubiś

Int. J. Mol. Sci. 2024, 25(7), 4072; https://doi.org/10.3390/ijms25074072 - 6 Apr 2024

Viewed by 1824

Abstract

Non-coding RNAs have been described as crucial regulators of gene expression and guards of cellular homeostasis. Some recent papers focused on vault RNAs, one of the classes of non-coding RNA, and their role in cell proliferation, tumorigenesis, apoptosis, cancer response to therapy, and autophagy, which makes them potential therapy targets in oncology. In the human genome, four vault RNA paralogues can be distinguished. They are associated with vault complexes, considered the largest ribonucleoprotein complexes. The protein part of these complexes consists of a major vault protein (MVP) and two minor vault proteins (vPARP and TEP1). The name of the complex, as well as vault RNA, comes from the hollow barrel-shaped structure that resembles a vault. Their sequence and structure are highly evolutionarily conserved and show many similarities in comparison with different species, but vault RNAs have various roles. Vaults were discovered in 1986, and their functions remained unclear for many years. Although not much is known about their contribution to cell metabolism, it has become clear that vault RNAs are involved in various processes and pathways associated with cancer progression and modulating cell functioning in normal and pathological stages. In this review, we discuss known functions of human vault RNAs in the context of cellular metabolism, emphasizing processes related to cancer and cancer therapy efficacy. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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36 pages, 3954 KiB

Open AccessReview

Non-Coding RNA-Targeted Therapy: A State-of-the-Art Review

by Francesco Nappi

Int. J. Mol. Sci. 2024, 25(7), 3630; https://doi.org/10.3390/ijms25073630 - 24 Mar 2024

Cited by 12 | Viewed by 2553

Abstract

The use of non-coding RNAs (ncRNAs) as drug targets is being researched due to their discovery and their role in disease. Targeting ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is an attractive approach for treating various diseases, such as cardiovascular disease and cancer. This seminar discusses the current status of ncRNAs as therapeutic targets in different pathological conditions. Regarding miRNA-based drugs, this approach has made significant progress in preclinical and clinical testing for cardiovascular diseases, where the limitations of conventional pharmacotherapy are evident. The challenges of miRNA-based drugs, including specificity, delivery, and tolerability, will be discussed. New approaches to improve their success will be explored. Furthermore, it extensively discusses the potential development of targeted therapies for cardiovascular disease. Finally, this document reports on the recent advances in identifying and characterizing microRNAs, manipulating them, and translating them into clinical applications. It also addresses the challenges and perspectives towards clinical application. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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40 pages, 1650 KiB

Open AccessReview

A Current Synopsis of the Emerging Role of Extracellular Vesicles and Micro-RNAs in Pancreatic Cancer: A Forward-Looking Plan for Diagnosis and Treatment

by Eleni Myrto Trifylli, Anastasios G. Kriebardis, Evangelos Koustas, Nikolaos Papadopoulos, Sotirios P. Fortis, Vassilis L. Tzounakas, Alkmini T. Anastasiadi, Panagiotis Sarantis, Sofia Vasileiadi, Ariadne Tsagarakis, Georgios Aloizos, Spilios Manolakopoulos and Melanie Deutsch

Int. J. Mol. Sci. 2024, 25(6), 3406; https://doi.org/10.3390/ijms25063406 - 17 Mar 2024

Cited by 3 | Viewed by 2108

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide, while it persists as the fourth most prevalent cause of cancer-related death in the United States of America. Although there are several novel therapeutic strategies for the approach of this intensely aggressive tumor, it remains a clinical challenge, as it is hard to identify in early stages, due to its asymptomatic course. A diagnosis is usually established when the disease is already in its late stages, while its chemoresistance constitutes an obstacle to the optimal management of this malignancy. The discovery of novel diagnostic and therapeutic tools is considered a necessity for this tumor, due to its low survival rates and treatment failures. One of the most extensively investigated potential diagnostic and therapeutic modalities is extracellular vesicles (EVs). These vesicles constitute nanosized double-lipid membraned particles that are characterized by a high heterogeneity that emerges from their distinct biogenesis route, their multi-variable sizes, and the particular cargoes that are embedded into these particles. Their pivotal role in cell-to-cell communication via their cargo and their implication in the pathophysiology of several diseases, including pancreatic cancer, opens new horizons in the management of this malignancy. Meanwhile, the interplay between pancreatic carcinogenesis and short non-coding RNA molecules (micro-RNAs or miRs) is in the spotlight of current studies, as they can have either a role as tumor suppressors or promoters. The deregulation of both of the aforementioned molecules leads to several aberrations in the function of pancreatic cells, leading to carcinogenesis. In this review, we will explore the role of extracellular vesicles and miRNAs in pancreatic cancer, as well as their potent utilization as diagnostic and therapeutic tools. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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19 pages, 2428 KiB

Open AccessReview

Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer

by Xueni Yang, Shizheng Xiong, Xinmiao Zhao, Jiaming Jin, Xinbing Yang, Yajing Du, Linjie Zhao, Zhiheng He, Chengjun Gong, Li Guo and Tingming Liang

Int. J. Mol. Sci. 2024, 25(3), 1561; https://doi.org/10.3390/ijms25031561 - 26 Jan 2024

Viewed by 1383

Abstract

Autophagy, a complex and highly regulated cellular process, is critical for the maintenance of cellular homeostasis by lysosomal degradation of cellular debris, intracellular pathogens, and dysfunctional organelles. It has become an interesting and attractive topic in cancer because of its dual role as a tumor suppressor and cell survival mechanism. As a highly conserved pathway, autophagy is strictly regulated by diverse non-coding RNAs (ncRNAs), ranging from short and flexible miRNAs to lncRNAs and even circRNAs, which largely contribute to autophagy regulatory networks via complex RNA interactions. The potential roles of RNA interactions during autophagy, especially in cancer procession and further anticancer treatment, will aid our understanding of related RNAs in autophagy in tumorigenesis and cancer treatment. Herein, we mainly summarized autophagy-related mRNAs and ncRNAs, also providing RNA–RNA interactions and their potential roles in cancer prognosis, which may deepen our understanding of the relationships between various RNAs during autophagy and provide new insights into autophagy-related therapeutic strategies in personalized medicine. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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41 pages, 3847 KiB

Open AccessReview

Trials and Tribulations of MicroRNA Therapeutics

by Attila A. Seyhan

Int. J. Mol. Sci. 2024, 25(3), 1469; https://doi.org/10.3390/ijms25031469 - 25 Jan 2024

Cited by 31 | Viewed by 10590

Abstract

The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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23 pages, 2366 KiB

Open AccessReview

Exosomes in the Diagnosis and Treatment of Renal Cell Cancer

by Stergios Boussios, Perry Devo, Iain C. A. Goodall, Konstantinos Sirlantzis, Aruni Ghose, Sayali D. Shinde, Vasileios Papadopoulos, Elisabet Sanchez, Elie Rassy and Saak V. Ovsepian

Int. J. Mol. Sci. 2023, 24(18), 14356; https://doi.org/10.3390/ijms241814356 - 20 Sep 2023

Cited by 21 | Viewed by 3240

Abstract

Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer originating from renal tubular epithelial cells, with clear cell RCC comprising approximately 80% of cases. The primary treatment modalities for RCC are surgery and targeted therapy, albeit with suboptimal efficacies. Despite progress in RCC research, significant challenges persist, including advanced distant metastasis, delayed diagnosis, and drug resistance. Growing evidence suggests that extracellular vesicles (EVs) play a pivotal role in multiple aspects of RCC, including tumorigenesis, metastasis, immune evasion, and drug response. These membrane-bound vesicles are released into the extracellular environment by nearly all cell types and are capable of transferring various bioactive molecules, including RNA, DNA, proteins, and lipids, aiding intercellular communication. The molecular cargo carried by EVs renders them an attractive resource for biomarker identification, while their multifarious role in the RCC offers opportunities for diagnosis and targeted interventions, including EV-based therapies. As the most versatile type of EVs, exosomes have attracted much attention as nanocarriers of biologicals, with multi-range signaling effects. Despite the growing interest in exosomes, there is currently no widely accepted consensus on their subtypes and properties. The emerging heterogeneity of exosomes presents both methodological challenges and exciting opportunities for diagnostic and clinical interventions. This article reviews the characteristics and functions of exosomes, with a particular reference to the recent advances in their application to the diagnosis and treatment of RCC. Full article

(This article belongs to the Special Issue Exosomes and Non-Coding RNA Research in Health and Disease)

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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Planned Paper: miRNome characterization of milk exosomes in cows treated with recombinant somatotropin - Dr. Alessandro Benedetto

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