A Bibliometric Analysis of Exosomes Associated with Rheumatic Diseases in the 21st Century

Yuanyuan Zou; Shuwei Wang; Xingyue Ao; Jialu Zhang; Enhao Chen; Jinping Wang; Jing Luo; Qingwen Tao

doi:10.2147/JMDH.S536183

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Original Research

A Bibliometric Analysis of Exosomes Associated with Rheumatic Diseases in the 21st Century

Authors Zou Y , Wang S, Ao X, Zhang J, Chen E, Wang J, Luo J , Tao Q

Received 23 April 2025

Accepted for publication 5 September 2025

Published 19 September 2025 Volume 2025:18 Pages 5977—6001

DOI https://doi.org/10.2147/JMDH.S536183

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr David C. Mohr

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Exosomes associated with Rheumatic Diseases – Video abstract [536183]

Yuanyuan Zou,^1,² Shuwei Wang,³ Xingyue Ao,³ Jialu Zhang,⁴ Enhao Chen,⁵ Jinping Wang,² Jing Luo,^2,^* Qingwen Tao^2,^*

¹Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; ²National Center for Integrative Medicine, Department of TCM Rheumatism, China-Japan Friendship Hospital, Beijing, People’s Republic of China; ³School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; ⁴Department of Rheumatology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; ⁵The Second Affiliated Hospital & Second Clinical Medical School, Jinhua Academy, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jing Luo; Qingwen Tao, National Center for Integrative Medicine, Department of TCM Rheumatism, China-Japan Friendship Hospital, No. 2 Yinghua East Road, Chaoyang District, Beijing, 100029, People’s Republic of China, Email [email protected]; [email protected]

Purpose: Numerous studies have suggested that exosomes are associated with rheumatic diseases, but no bibliometric analysis has been performed. This study presents the first comprehensive bibliometric analysis aiming to evaluate the current research hotspots and to anticipate future trends.
Methods: An electronic search was conducted in the Web of Science Core Collection (WOSCC) using exosome and rheumatic disease-specific terminology to identify eligible studies published from January 1, 2000 to October 19, 2024. Only English-language articles and review articles were selected for bibliometric analysis. Data analysis and visualization were conducted using CiteSpace 6.2.R3, VOSviewer 1.6.18, and the Bibliometrix R package.
Results: A total of 1,251 publications with 49,374 citations were extracted from the WOSCC database. Both publication and citation frequency increased steadily. 255 different countries or regions, 4,413 institutions and 7,213 authors contributed to the field. China and the USA are the leading countries and Shanghai Jiao Tong University has a significant influence. Théry C is the most frequently co-cited researcher. Most papers are published in Frontiers in Immunology, while Stem Cell Research & Therapy has the highest citations. Research is primarily concentrated in cell biology, immunology, and experimental medicine. Exosm, mesenchymal stem cells (MSCs), autoimmunity, regeneration, and others are major areas of research in this field. Research hotspots primarily focus on the diagnostic potential and therapeutic applications of exosomes in osteoarthritis and rheumatoid arthritis. Exosomes derived from MSCs and their cargo, such as microRNAs (miRNAs), have the potential to serve as biomarkers and therapeutic vehicles in these diseases.
Conclusion: This study firstly quantifies and identifies the current status and research frontiers of exosomes in RDs by using bibliometric analysis, which may provide valuable insights for researchers to navigate trends and emerging applications into the field.

Keywords: bibliometric, exosomes, osteoarthritis, rheumatoid arthritis, mesenchymal stem cells

Introduction

Exosomes are endocytic membrane-derived vehicles that ranging from 30 to 120 nm in size, identified as key mediators in intercellular communication.¹ Released by a variety of cell types, these vehicles are consistently found in bodily fluids such as breast milk, urine, plasma, and saliva.² Exosomes carry a diverse cargo, including proteins, lipids, DNA, and various RNA species.³ Originating in endosomes, their biogenesis involves interactions with other intracellular vesicles and organelles, shaping their final content.⁴ Each exosome reflects the characteristics and functions of its parent cell. The unique biological properties of exosomes enable them to protect internal biomolecules from deterioration and evade immune clearance, allowing for the delivery of more effective cargo with potential therapeutic targeting effects.⁵ Moreover, exosomes can penetrate various biological barriers, including the blood-brain barrier, while their associated toxic side effects are minimized.^6,7

Rheumatic diseases (RDs) encompass a range of disorders primarily targeting the musculoskeletal system, directly affect bones, joints, muscles, connective tissues, and periarticular soft tissue.⁸ The primary pathobiological characteristic of many RDs is the development of an excessively self-reactive, antigen-driven immune response, which contributes to the complex inflammatory processes and tissue damage.⁹ Due to the chronic nature of these disorders and the frequent adverse effects of conventional treatments, patients often seek complementary and alternative therapies, hoping for “less toxic” remedies.¹⁰ Exosomes have been extensively studied for their role in RDs, particularly in relation to autoimmune and inflammatory conditions such as rheumatoid arthritis (RA), osteoarthritis (OA), and systemic lupus erythematosus (SLE). Exosomes derived from mesenchymal stem cells (MSCs), synovial fluid (SF), or immune cells carry proteins, lipids, and nucleic acids capable of modulating immune responses and tissue repair. Long non-coding RNAs (lncRNAs) in exosomes have been implicated in the pathogenesis of RA through the nuclear factor kappa B (NF-κB) and Wnt signaling pathways, with the resulting imbalance in Th17/Treg cell production contributing to synovial cell damage.¹¹ Exosome-derived miRNAs, such as miR-451a and miR-25-3p, are promising candidates for early diagnosis of RA.¹² Additionally, exosomal miR-26b-5p regulates the polarisation of macrophages and the hypertrophy of chondrocytes in OA.¹³ Exosomes also help determine the cellular origin of disease onset. In the synovial fluid of patients with inflammatory arthritis, the most common exosomes are derived from platelets, T cells and B cells.¹⁴ Exosomes from various sources demonstrate potential diagnostic and therapeutic effects in RDs. MSCs-derived exosomes have been shown to modulate immune responses and exhibit immune suppressive effects. Exosomal miR-16 and miR-21 secreted by bone marrow mesenchymal stem cells (BMSCs), as well as miR-146a-5p from umbilical cord mesenchymal stem cell (UC-MSCs) exosomes, promote the transition of macrophages to an anti-inflammatory M2 macrophage phenotype, thereby inhibiting the inflammatory response.¹⁵ Exosomes are recognized as emerging leaders in regenerative medicine.¹⁶ The integration of exosomes with biomaterials, such as hydrogels, has emerged as a novel therapeutic strategy. This approach not only lubricates joints but also serves as a drug delivery system, enabling sustained release of therapeutic agents.^17,18 Additionally, engineered exosomes modified with specific bioactive molecules can regulate corresponding target proteins, thereby enhancing anti-inflammatory and immunomodulatory effects.¹⁹ For example, engineered exosomes overexpressing miR-140 target calpain 1, modulate mitophagy, and ameliorate OA progression via intra-articular delivery.²⁰ In conclusion, exosomes can influence RDs through various pathways.

Bibliometrics is a field of quantitative analysis applied to scholarly literature, capable of mapping intellectual structures, identifying research trends, and assessing scholarly impact. Its core value lies in providing a systematic method to measure and evaluate the vast output of scientific research, offering insights on the evolution of research and the interconnections between various research domains. However, recent studies suggested that exosomes hold significant potential in the treatment of RDs, and bibliometric analysis on exosomes in RDs have not yet emerged. This study aims to address this gap by performing a bibliometric analysis of exosomes associated with RDs in the 21st century. Our objective is to evaluate the current state of research to gain a better understanding of the research dynamics in this field. Additionally, we seek to predict future thematic development and research priorities by examining research trends and hotspots. This analysis will also emphasize the impact of exosomes on the diagnosis and treatment of OA and RA, underscoring the importance of continued research in this field.

Methods

Search Strategy and Data Collection

The literature source for this analysis is the Web of Science Core Collection (WOSCC), which is recognized for its comprehensive and standardized coverage of international scientific literature. The search strategy utilized the following search string: (TS=(“rheumatic disease” OR “rheumatology” OR “rheumatism” OR “rheumatoid arthritis” OR “psoriatic arthritis” OR “osteoarthritis” OR “gout” OR “pseudogout” OR “arthritis” OR “Takayasu arteritis” OR “ankylosing spondylitis” OR “spondyloarthropathy” OR vasculitis OR “granulomatosis with polyangiitis” OR “Wegener granulomatosis” OR “microscopic polyangiitis” OR “Behçet” OR “systemic lupus erythematosus” OR “Sjogren’s syndrome” OR “systemic sclerosis” OR “scleroderma” OR “connective tissue disease” OR “autoimmune disease” OR “myositis” OR “polymyositis” OR “dermatomyositis” OR “idiopathic inflammatory myositis” OR “antiphospholipid syndrome” OR “fibromyalgia” OR “Still’s disease” OR “polymyalgia rheumatica”)) AND TS=(“exosomes” OR “exosome” OR “exosomal”). The time frame was restricted to the 21st century (January 1, 2000 to October 19, 2024). Only articles and review articles published in English were considered to maintain the academic rigor and linguistic consistency of the analysis. Duplicates were removed using CiteSpace. All highly cited papers indexed by the WOSCC were extracted into a table format. The data were downloaded and verified independently by two researchers (YYZ and SWW) to assure the accuracy of the study. Any discrepancies were addressed through the third-party (XYA). The flow chart depicted in Figure 1 illustrates the data extraction and analysis process.

Figure 1 The flow chart for data extraction and analysis process.

Data Analysis and Visualization

We use CiteSpace 6.2. R3, VOSviewer 1.6.18, and Bibliometrix R packages to conduct data analysis and visualization of the countries or regions, institutions, authors, journals, keywords, and references involved in this field. CiteSpace is renowned for its ability to visualize citation networks, knowledge structures, research fronts, and trends in scientific domains.²¹ Node size indicates relative proportion and line thickness shows connection strength.²² It provides a range of metrics to assess the significance of nodes within a network. Temporal metrics like citation burst indicate periods of abrupt change in the frequency of an entity, highlighting emerging terms.²³ Structural metrics such as centrality, modularity, and silhouette score are used. Nodes with high centrality (≥ 0.1) generally connect different clusters and are quantitatively considered pivotal in network analysis. The modularity and silhouette metrics, namely the Q value and the S value, are important for assessment. Generally, the Q value ranges from 0 to 1, and the S value ranges from −1 to 1. Low Q value indicates fuzzy clusters, while high Q value indicates clear cluster structure. The Q value greater than 0.3 indicates the identified community structure is significant. The S value exceeding 0.7 considered high credibility and exceeding 0.5 considered reasonable. If the S value approaches 1, the cluster is perfectly separated from others. If the S value approaching 0 suggests ambiguous cluster boundaries, and approaching −1 suggests invalid partitioning.²⁴ VOSviewer is a software tool designed for creating and visualizing bibliometric networks. Node size indicates item frequency, line thickness represents the strength of association, and colors distinguish thematic clusters.²⁵ Bibliometrix is an R package designed for comprehensive science mapping analysis, providing a suite of tools for quantitative research in bibliometrics and scientometrics. This package supports three key phases of analysis: data importing and conversion to R format, bibliometric analysis of a publication dataset, and building and plotting matrices for co-citation, coupling, collaboration, and co-occurrence analysis.²⁶

Results

Analysis of Publication Outputs and Growth Trend Predictions

Annual publications can reflect research progress and trends in the field. From 2000 to 2024, a total of 1,251 publications were extracted from WOSCC database, including 780 articles and 471 reviews. As of October 19, 2024, these articles received 49,374 citations, equating to an average of 39.47 citations per article. As shown in Figure 2, the overall publication trend has increased since the 21st century. In 2020, the number of papers grew rapidly, reaching 100 for the first time. Since then, there has been an exponential increase in the number of papers each year. Moreover, as demonstrated in Supplementary Figure 1, the dominance of research articles within this growth continues and even increases. Additionally, citation frequency has increased significantly. The fitting equation for publications was y =0.8623e°.^2157x, and the simulation curve clearly indicates a relatively strong coefficient of determination (R² = 0.8987), which suggests that the number of annual articles is expected to steadily increase.

Table 1 The Top 10 Countries or Regions of the Number of Publications and Frequency of Citations

Figure 2 The annual publication, annual citation frequency, and the growth trend prediction.

Analysis the Network of Cooperation Across Countries or Regions and Institutions

A total of 255 different countries or regions were extracted from our database. The top 10 countries with the highest number of publications and citations are reported in Table 1. China was the most productive country (n = 699, 55.88%), followed by the USA (n = 205, 16.39%), Italy (n = 67, 5.36%). Meanwhile, China has established a leading position in terms of citation frequency and H-index, indicating its significant contribution to the development of this field and its extremely high degree of influence. Figure 3A illustrates the collaborative network between countries or regions. Supplementary Table 1 shows the top three countries or regions with high centrality are the USA (0.45), Germany (0.22), and China (0.22). The burst intensity revealed that the USA had the biggest strength, and the longest citation burst (2000 to 2018, strength 23.66) (Supplementary Figure 2). These analysis highlight that the global research focus is primarily on the function of exosomes and potential therapeutic applications in RDs (like cartilage repair and regeneration).^27,30

Figure 3 The network map of cooperation between countries or regions (A) and institutions (B).

Notes: Data for the “Taiwan” region is included within “People’s Republic of China”.

An analysis of 4,413 institutions shows that the primary research institutions in this field are primarily based in China. The visual analysis reveals that Shanghai Jiao Tong University holds significant influence in the field, which published 43 articles with 2,694 citations, with an average of 62.65 citations per article and an H-index of 19. Furthermore, although the Pennsylvania Commonwealth System of Higher Education published only 20 articles, with an average citation of 160.45, far surpassing the other institutions (Table 2). At the same time, Supplementary Table 1 indicates that it is also the institution with the highest centrality. Figure 3B demonstrated that network collaboration between institutions. Radboud University Nijmegen showed the strongest citation burst (2001 to 2007, strength 7.9) (Supplementary Figure 2).

Table 2 The Top 10 Institutions of the Number of Publications and Frequency of Co-Citations

Analysis the Network of Authors and Co-Citation Authors

Analyzing authors’ contributions provides a straightforward means of identifying academic pioneers in the field. Using VOSviewer, we visualize an extensive analysis of 7,213 authors as shown in Figure 4. To enhance the clarity of the visualization, Figure 4A demonstrated a collaborative network analysis on a subset of 85 authors, each having at least 11 publications, ultimately forming 18 clusters. Cluster #1 (red) is the largest, comprising 11 items. Cluster #2 (green) forms a collaborative network centered around professors Liang Yujie, Duan Li, and Xu Xiao from Shenzhen University, who are also the top three contributors in terms of publication count. Their research emphasizes the role of exosomes as effective carriers for delivering miRNA into chondrocytes in osteoarthritis treatment.^31,35 Cluster #3 (blue) primarily consists of researchers hailing from IRCCS Institute Orthopedic Galeazzi, with De Girolamo, Laura as the central figure, and their primary research focus on adipose-derived mesenchymal stem cells (ASCs)-extracellular vehicles (EVs).^36,38 Cluster #4 (yellow) is centered on Toh Wei Seong from the National University of Singapore, who proposed MSCs exosomes could mediate M2-like macrophage polarization in the immunoregulatory mechanism.³⁹ Notably, Table 3 highlights Toh Wei Seong ranks 4th in publication count and is the only author in the top 10 by publication output who also ranks within the top 10 for citation frequency. It is evident that active cooperation occurs within the same cluster, whereas cross-cluster collaboration is not discernible. Figure 4B demonstrates that Théry C is the most frequent co-citations author, with work indicating that exosomes possess a unique molecular composition and potent immunostimulatory properties,²⁹ followed by Zhang S, Tao S, and Cosenza S. The authors were primarily grouped into 4 clusters in the co-citation network, namely Théry C, Raposo G, Kim Sh, etc. from cluster #1 (red); Zhang Sp, Tao Sc, Cosenza S, Mao Gp, Toh Ws, etc. from cluster #2 (blue); Zhang Y, Kalluri R, etc. from cluster #3 (green); Lai Rc, etc. from cluster #4 (yellow). Cluster #1 (red) and cluster #2 (blue) focus on clinical research involving mesenchymal stem cells-derived exosomes for the prevention and treatment of inflammatory arthritis.^40,43

Table 3 The Top 10 Authors of the Number of Publications and Frequency of Co-Citations

Table 4 The Top 10 Journals and Co-Cited Journal

Figure 4 The visualization map of authors’ co-authorship (A) and co-citation (B).

Analysis of Journals, Co-Citation Journals, and Research Categories

To assess the impact and academic status of journals in this field, we performed a visual analysis of the journals. As shown in Table 4 and Figure 5A, the journal with the highest number of publications is Frontiers in Immunology (n = 63, 5.04%), followed by International Journal of Molecular Sciences (n = 54, 4.32%) and Stem Cell Research & Therapy (n = 30, 2.40%). Among the top 10 productive journals, there were 7 journals ranked in Q1 according to Journal Citation Reports (JCR), 5 of which had an impact factor (IF) higher than 5. The journal with the highest citation is Stem Cell Research & Therapy (n = 2248), followed by Journal of Immunology (n = 1691), and International Journal of Molecular Sciences (n = 1684). Notably, the top three most productive journals also rank highly in terms of citation frequency, underscoring their significant academic influence, which may be attributed to their broad academic coverage. Additionally, we conducted an analysis of the top 20 research categories in this field, as depicted in Figure 5B. The primary research areas are focused on cell biology, immunology, experimental medicine research, biochemistry, and molecular biology. To explore the thematic distribution and citation trajectories of academic journals, we used a dual-map overlay of journals to highlight the extensive communication across interdisciplinary fields. This visual representation illustrates the citation connections between two distinct sections: the left side denotes the citing journals, while the right side denotes the cited journals. Figure 5C shows that journals within the realms of Molecular/ Biology/ Genetics are frequently cited by journals from Molecular/ Biology/ Immunology and Medicine/ Medical/ Clinical, illustrating the translation of basic research into clinical research.

Figure 5 The analysis of journals, co-citation journals, and research categories. (A) Core Source Journals Identified by Bradford’s Law. (B) Nightingale rose chart of the top 20 research categories. (C) A dual-map overlay of the journals.

Analysis of Co-Occurrence Keywords

A meticulous analysis of keywords was conducted to vividly identify the active research areas, the emerging trends, the development of new knowledge domains, and the relationships between different topics in this field. Figure 6A reveals a total of 372 nodes and 706 edges. The top three most prominent keywords are extracellular vesicles (n = 390), exosm (n = 316), and mesenchymal stem cells (n = 310), probably due to our search strategy. Exosomes are a subset of extracellular vesicles, but in many cases, the terms “exosomes” and “extracellular vesicles” are used interchangeably.⁴⁴ Exosomes derived from MSCs have garnered widespread attention due to their potential in tissue repair and regenerative medicine. The work of Zhang S is particularly representative. They discovered that exosomes from MSCs can promote cartilage regeneration through multiple mechanisms, including enhancing proliferation, reducing apoptosis, modulating immune responsiveness, and restoring matrix homeostasis.^30,43,45 Rheumatoid arthritis (n = 215) and osteoarthritis (n = 161) are the most extensively studied diseases. The keyword “expression” exhibits the highest centrality score of 0.54 within this network. Its high-cited articles indicate that exosomes from various sources, carrying specific molecular expressions such as miRNAs and proteins, have therapeutic potential in modulating pathological states and improving disease symptoms.^46,48 Supplementary Table 2, indicate that the keyword analysis also encompasses various laboratory indicators, including the pathological mechanisms of disease (such as inflammation),⁴⁹ construction of experimental models (such as collagen-induced arthritis models),^50,51 detection methods (such as in vitro or vivo experiments),⁵² and indicators to assess therapeutic efficacy (such as vascular endothelial growth factor).⁴⁶ “Regeneration” is a key word widely used in clinical treatment. MSCs have been recognized as a rational therapeutic strategy in regenerative medicine. However, compared with MSCs, exosomes derived from MSCs offer a more stable and controllable therapeutic entity. This innovative research direction has opened new avenues for the development of regenerative medicine.⁵³

Figure 6 The analysis of co-occurrence keywords. (A) The network visualization map of keywords. (B) The timeline view of keywords cluster.

Keywords were classified into 13 clusters as shown in Figure 6B, including cluster #0 human pm scl, cluster #1 cancer, cluster #2 fas ligand, cluster #3 regenerative medicine, cluster #4 systemic sclerosis, cluster #5 chondrocytes, cluster #6 extracellular vesicles, cluster #7 expression, cluster #8 rheumatoid arthritis, cluster #9 dendritic cells, cluster #10 mesenchymal stromal cells, cluster #11 mesenchymal stem cell, cluster #12 microparticle. The keyword cluster timeline boasted a modularity Q value of 0.7796 and a mean silhouette S value of 0.9033, which signifies a well-structured and interconnected field.²⁴ The timeline reveals a dynamic and evolving research field, with a clear progression from basic science to translational and therapeutic research. It highlights the multidisciplinary nature in this field, encompassing immunology, cell biology, and regenerative medicine, with a growing emphasis on the role of exosomes in disease pathogenesis and potential therapeutic applications. Supplementary Figure 3 showed the keyword citation burst analysis from 2000 to 2024. The keyword “dendritic cells” shows the strongest citation burst (2006 to 2018; strength 18.03). The keyword with the longest duration is “autoantibody” and “autoimmune disease” for lasting 14 years.

Table 5 The in-Depth Impact of Exosomes Sourced From Various Types on OA

Table 6 The in-Depth Impact of Exosomes Sourced From Various Types on RA

Therefore, we have made a systematic summary of the expression of exosomes in RDs, presented in Table 5 and Table 6, showing that exosomes are significantly expressed in specific RDs, particularly OA and RA. Current research is mainly conducted in animal models and other basic studies. The functions of exosomes vary depending on their source and the cargo they carry, with most exosomes originating from MSCs and expanding their functions beyond their inherent roles. Exosomes can carry a variety of cargoes, the most important of which are miRNAs, which regulate the expression of various protein-coding genes. The expression of exosomes in RDs involves multiple biological mechanisms and pathways, providing a basis for the development of new therapeutic strategies and potentially improving the treatment outcomes of RDs. These findings not only reveal the current research focus but also may provide significant insights into predicting the future development trends of the field.

Table 7 The Top 10 Most Cited References

Analysis of Co-Citation References

A co-citation analysis was conducted to elucidate the structural relationships among citations and to provide insights into the development trends and interdisciplinary connections within the field.¹⁵⁰ Table 7, extracted from the WoSCC database, presents a quantitative summary of the most influential research in the field. The number of citations range from 1,652 to 514, with most influential works originating from the USA. Figure 7A showed the most highly cited article is “Regulation of immune responses by extracellular vehicles” by Robbins, PD, published in 2014 in Nature Reviews Immunology (n = 1652). It provides an in-depth examination of the intricate mechanisms through which extracellular vesicles regulate immune responses. It underscores their potential as therapeutic targets or diagnostic markers in immunological disorders.⁵⁰ The second-ranked article is “Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles” by György, B (n = 1622), which emphasize the burgeoning role of extracellular vesicles in mechanisms of intercellular communication and immune regulation.¹⁴⁶ The main content of highly co-cited references emphasizes the powerful immunomodulatory functions of exosomes. In addition, exosomes also serve as potential biomarkers and therapeutic vehicles, with clinical applications in treating and preventing various inflammatory diseases. The article “Exosome: from internal vesicle of the multivesicular body to intercellular signaling device” by Denzer K has the highest centrality score of 0.32, as shown in Supplementary Table 3. The second ranking is the article “Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells” by Valadi H (0.31). They reveal the physiological functions and characteristics of exosomes. For instance, follicular dendritic cells can bind to B-lymphocyte-derived exosomes on their cell surface.¹⁵¹ Exosomes contain mRNAs and microRNAs. These RNAs can be delivered to other cells and translated into proteins within the recipient cells, facilitating the transfer of information between cells.¹⁵² These articles are distributed across various journals, reflecting their relevance to immunology, oncology, rheumatology, regenerative medicine, and other disciplines.

Figure 7 The analysis of co-citation references. (A) The network visualization map of co-citation references. (B) The cluster visualization map of co-citation references.

The network shown in Figure 7 is pruned at a level that ensures the most significant connections, highlighting several key nodes and clusters that represent the central concepts and research foci within this domain, the modularity Q value of 0.7877 and a mean silhouette S value of 0.9095. Figure 7B identified 13 clusters, based on their content, these clusters were divided into two research directions. The first major research area encompasses RDs, represented by cluster #0 osteoarthritis, cluster #7 rheumatoid arthritis, and cluster #14 complications. Cluster #0, the largest cluster, focuses on the role of exosomes in promoting cartilage tissue regeneration and preventing osteoarthritis. The second principal research direction delves into the function and applications of exosomes in RDs. These clusters can be systematically categorized into three overarching groups: Molecular and cellular biology: cluster #2 reference genes, cluster #3 microparticles, cluster #9 microparticle, cluster #8 exocrine dysfunction, cluster #10 apoptotic bodies, and cluster #11 endosome; Immunology-related: cluster #1 autoimmunity, cluster #4 autoantibodies, cluster #12 toll-like receptor 4; Therapeutic applications: cluster #5 regeneration. The results of co-citation reference cluster align with the keyword analysis, revealing that research in this field is primarily concentrated on specific RDs. Research on exosomes spans multiple domains including genetics, cell biology, and molecular biology. In addition, the role of exosomes in immune responses and applications in regenerative medicine also shows great potential.

Discussion

In the 21st century (from 2000 to 2024), a total of 1251 publications and 49,374 citations related to RDs and exosomes were extracted from WOSCC database. The trend of annual publications and citations is expected to steadily increase. Notably, there was a rapid surge in the number of publications in 2020, which can be attributed to the widespread COVID-19 pandemic. This global health crisis has intensified the focus on autoimmune health,¹⁵³ as patients with rheumatic diseases are more susceptible to contracting COVID-19 compared to the general population.¹⁵⁴ The increased dominance of research articles throughout the pandemic years is also notable It suggests that research in this area, potentially involving bioinformatics or experimental modeling, demonstrated resilience in the face of laboratory restrictions. However, additional factors, such as governmental healthcare policies, must also be considered in this context. Research on this topic spans 255 countries or regions and 4,413 institutions. China and the USA are leading contributors, with Chinese institutions such as Shanghai Jiao Tong University and Central South University dominating the number of publications. Based on the analysis of the authors and co-cited authors, Liang, Yujie is the most productive author, with the top three authors with the highest number of publications. Théry C stands out as the most frequently cited researcher. We have identified Frontiers in Immunology, International Journal of Molecular Sciences, Stem Cell Research & Therapy, and Journal of Immunology as the core journals in this field. The dual-map overlay of journals suggests that clinical medical research requires a foundation in experimental studies in molecular biology, biotechnology, and genetics. Combining insights from the WOSCC database, the main research directions in this field focus on cell biology and immunology.

Through a detailed analysis of keywords and co-cited reference, the research focus and future development trends in the field during the 21st century can be discerned. As research progresses, the mysteries of exosomes are gradually being unveiled. Particularly, reference cluster analysis (such as cluster #3, cluster #8, cluster #9, and cluster #10) and co-citation reference centrality analysis both indicate that the composition, physiological characteristics, and applications of exosomes are the current focus of this field. Our research reveals that Théry C. is the most frequently cited author. As a leading figure in exosome research, she has revealed that exosomes play a crucial role in altering gene expression and intracellular signaling pathways in the recipient cells by transporting RNA, lipids, and proteins. Exosomes are captured by neighboring recipient cells through the interaction of vesicular ligands with cellular receptors, thereby participating in the transmission of biological signals and the regulation of various biological processes.^155,157 Each exosome is an extension of the characteristics and functions of its original cell. Exosomes function as vehicles for antigen presentation in immune responses, regulating the activation and signaling of immune cells.¹⁵²

Keyword analysis revealed that “mesenchymal stem cells” exhibited a higher frequency of occurrence, and the top two keywords by centrality score were “expression” and “cell-derived exosomes”, collectively indicating that research into MSC-derived exosomes is a current hotspot. Together with the results of the co-citation reference analysis (such as cluster #0 and cluster #7), recent studies demonstrate that in order to address the severe threat posed by RDs such as OA and RA, researchers are turning their attention to the potential of exosomes in disease diagnosis and treatment. Given the high prevalence and severe clinical outcomes of these diseases, inflammation and immune dysregulation are well-established pathogenic mechanisms. Exosomes can mediate disease progression and serve as therapeutic targets by participating in various pathological processes. As indicated by the dual-map overlay results, the knowledge trajectory in this field demonstrates a transition from basic research towards clinical research. Therefore, researchers have focused their attention on these diseases. Additionally, the availability of experimental models, accessibility of clinical samples, and substantial government funding are also key factors that have driven the research in this area.

The pathogenesis of OA is complex, with many pathological manifestations including synovial inflammation, ligament degeneration, subchondral bone remodeling, cartilage damage, and changes in the neuromuscular structures around the joints. The main factor leading to OA is a high level of inflammation. Inflammation plays a pivotal role in driving cartilage progression and bone destruction.¹⁵⁸ T lymphocytes and macrophages are the primary inflammatory cells involved in the pathogenesis of OA. Inflammatory fibroblast-like synoviocytes derived exosomes (FLS-exos) aggravate inflammation and M1 polarization in macrophage. Increased levels of the inflammatory response promote immune cell infiltration, proliferation, and angiogenesis, leading to further joint damage.¹⁵⁹ Synovial fluid-derived exosomes (SF-exos) contribute to the onset and progression of OA by promoting the activation of pro-inflammatory M1 macrophages and inducing the production of IL-1β along with other inflammatory cytokines. It also upregulated the levels of matrix metalloproteinase (MMP), leading to the degradation of the chondrocyte extracellular matrix (ECM).¹⁶⁰ Exosomes can modulate OA through their encapsulated cargo, such as miRNA and lncRNA. They may also serve as promising biomarkers, such as hsa_circ_0104873, which significantly increased in the SF of OA patients.¹⁶¹

RA is characterized by synovial hyperplasia, immune cell infiltration, and autoantibody production. The immune pathogenesis of RA is related to an imbalance between memory Th17 and memory regulatory T cells. As antigen-presenting carriers, exosomes in the SF of RA patients contain citrullinated proteins that are recognized by anti-citrullinated peptide antibodies, a hallmark of RA. This recognition initiates an inflammatory response characterized by the proliferation of Th1 and Th17 cells, ultimately leading to joint damage.¹⁶² During the active phase of RA, plasma exosomes increase the release of pro-inflammatory cytokines such as IL-1, TNF, and IL-17.¹⁶³ Exosomes contribute to joint destruction and inflammatory processes: various nucleic acid components carried by exosomes, such as high levels of miR-221-3p and circFTO in FLS-exos, can damage bone and cartilage.^142,164 The lncRNA in exosomes can activate the NF-κB and Wnt signaling pathways, leading to Th17/Treg centered inflammation and resulting in synovial cells damage.¹⁶⁵ On the other hand, exosomes derived from inflammatory FLS can induce macrophages M1 polarization, generating a pro-inflammatory response.¹⁶⁶ Additionally, studies have shown that exosomes from RA patients carrying the co-inhibitory receptor PD-1 and related miRNAs can induce T cell exhaustion, leading to the progression of RA into a chronic disease.¹⁶⁷ Furthermore, circulating exosomal miRNA and serum exosomal lncRNA may be valuable biomarkers for RA.^168,170

Exosomes are double-edged swords in biological processes. While implicated in the pathogenesis of RDs, they also hold significant therapeutic potential. Exosomes from diverse sources, carrying various cargos, exhibit distinct therapeutic effects on RDs. MSCs have been widely used as immunosuppressants and are emerging as a research hotspot in regenerative medicine. Studies have demonstrated that MSC-Exos possess anti-apoptotic, anti-inflammatory, and regenerative effects in RDs.¹⁷¹ MSC-exos can rescue cartilage injury and regulate macrophage polarization by reducing ferroptosis, a form of iron-dependent cell death implicated in OA.^57,141 Exosomes can promote cartilage regeneration and mitigate cartilage degradation. Synovial MSCs derived exosomes (SMSC-exos) regulate bone regeneration and significantly promote cartilage repair through the Wnt5a/Wnt5b/YAP pathway.⁴¹ BMSC-Exos inherit the anti-inflammatory property of BMSCs, inhibiting macrophage activation reducing IL-1β levels and alleviating chondrocyte apoptosis.⁵⁵ Furthermore, Platelet-rich plasma derived exosomes (PRP-exos) can activate the Wnt/β-catenin signaling pathway, reduce pro-inflammatory factor IL-1β levels, and alleviate joint t inflammation.¹²⁴ FLS from RA patients exhibit an aggressive phenotype that causes damage to cartilage and bone.¹⁷² Components such as Fibrinogen-like protein 1 (FGL1) and miR-143-3p contained in MSC-exos can inhibit RA-FLS activation by reducing the activity of the NF-κB pathway.^126,132 Additionally, SMSC-exos inhibit signal transducer and activator of transcription 1 (STAT3) activity and downregulate vascular endothelial growth factor (VEGF) complex expression, resulting in reduced angiogenesis.¹³⁷ BMSC-exos have also been shown to exert anti-inflammatory effects by dose-dependently inhibiting T lymphocyte proliferation and reducing the CD4+ and CD8+ T cell ratio.¹⁷³ It also ameliorates inflammation by preventing the release of NLRP3 (NLR family pyrin domain-containing 3) in RA rats.¹²⁹ UMSC-exos have demonstrated the ability to reduce the Th1/Th17 to Treg cell ratio.¹³⁶

However, despite the potential applications of exosomes in RDs, several challenges that need to be addressed. Standardization and validation of products are major challenges. Current isolation techniques, such as ultracentrifugation, and the purity of exosomes produced by different methods, may affect the quality and efficacy of exosomes.¹⁷⁴ Exosomes can modulate the activity of recipient cells and therefore have potential immunogenicity and tumorigenicity. However, compared to MSCs, exosomes, as cell-free vesicles, significantly reduce immunogenicity.¹⁷⁵ Moreover, Heterogeneity in exosome yield and cargo composition between different batches and cell sources further complicates their clinical application. The keyword analysis timeline shows that the popularity of regenerative medicine research has increased significantly in recent years. Regenerative medicine is poised to emerge as the next frontier in this field, with the potential to lead to significant breakthroughs in the treatment of RDs. One promising therapeutic strategy is the bioengineering of exosomes, which exhibit enhanced targeting, retention and stability.¹⁷⁶ For example, engineered exosomes surface-modified with a chondrocyte-affinity peptide (CAP) and loaded with nuclear factor E2-related factor 2 (Nrf2) facilitated targeted delivery to cartilaginous endplate cells by inhibiting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission.¹⁷⁷ Another innovative approach indicates that engineered exosomes loaded with triptolide can inhibit RA fibroblast proliferation and demonstrate lesion-targeting specificity, enhancing therapeutic efficacy.¹⁷⁸ In addition, pH-responsive engineered exosome can reprogram chondrocytes to sustainably produce endogenous hyaluronic acid (HA), enhancing cartilage regeneration.¹⁷⁹ To further optimize delivery efficiency, encapsulating exosomes into biomaterials like hydrogels enhances bioavailability and enables spatiotemporally controlled release, promoting cartilage protection and regeneration.^180,181 Superoxide dismutase 3 (SOD3)-rich exosome-loaded hydrogel microspheres reduce reactive oxygen species (ROS) and enhance ECM synthesis in OA.¹⁸² Moreover, magnetic polysaccharide hydrogel microcarriers co-deliver stem cell exosomes and diclofenac sodium to repair cartilage and alleviate OA symptoms.¹⁸³

Bibliometrics analysis is a valuable tool for assessing academic impact and identifying trends, but it also has its limitations. Firstly, bibliometric indicators represent only one aspect of research evaluation and do not provide a comprehensive overview of research results. Secondly, bibliometrics methods may not always accurately capture emerging and interdisciplinary fields, as the body of literature is constantly evolving, and it often takes time for progress to be reflected in the data. Thirdly, relying solely on the WOSCC database for data collection may limit the interpretation of the results. However, most databases, such as PubMed, do not always provide complete references and citations for articles. Fourthly, the presence of homonymous authors could introduce errors in the author analysis, affecting the accuracy of the results. Finally, the language of the included literature is limited to English and the article types are restricted to articles and review articles, potentially excluding important articles. However, this limitation is inherent in the software used for the analysis.

Conclusion

In conclusion, this bibliometric analysis provides a comprehensive landscape of exosomes in RDs in the 21st century. The steady upward trend in publications and citations reflects the growing interest in the field. China and the USA emerge as prominent contributors. Théry C is the most frequently co-cited author and has a significant impact. Core journals like Frontiers in Immunology, International Journal of Molecular Sciences, and Stem Cell Research & Therapy suggest that the primary research foci are rooted in cell biology, immunology, and experimental medicine. This study highlights the dual role of exosomes in disease pathogenesis and treatment. The burgeoning interest in exosomes as key players in the progression of OA and RA, with the potential to serve as biomarkers and therapeutic vehicles, such as modulating immune dysregulation, cartilage degradation, and inflammatory responses. It also bridges basic science with clinical applications, providing a basis for regenerative medicine applications, such as engineering exosomes. Therefore, our analysis may foster the development of the field and help scholars to navigate the intellectual architecture of research frontiers of exosomes in RDs. Compared with other diseases, the research on the pathogenesis and therapeutic strategies of exosomes in RDs is relatively limited. Further studies are still required to elucidate the exact mechanisms of exosomes in RDs, which will provide novel insights for disease diagnosis and treatment.

Ethics Approval and Informed Consent

The manuscript does not contain clinical studies or patient data. The data were obtained directly from the database without any additional human or experimental animal involvement, so there was no need for ethical approval.

Author Contributions

Jing Luo and Qingwen Tao contributed equally and shared corresponding authorship. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This work was supported by Capital’s Funds for Health Improvement and Research (Grant number: 2024-1-4065); Elite Medical Professionals Project of China-Japan Friendship Hospital (Grant number: ZRJY2024-GG08); Rheumatology Branch of China Association of Chinese Medicine Youth Pei Ying Project (Grant number: 202327-007).

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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