Global trends and future perspectives on exosomes in colorectal cancer: a comprehensive bibliometric analysis (2003-2024)

Global trends and future perspectives on exosomes in colorectal cancer: a comprehensive bibliometric analysis (2003-2024) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Global trends and future perspectives on exosomes in colorectal cancer: a comprehensive bibliometric analysis (2003-2024) Man Lu, Yanjie Jiang, Lili Song, Chun Xu, Jialin Gao, Meilin Yang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6450425/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Colorectal cancer (CRC) is one of the most frequent malignant tumors in the world. Its pathogenesis is complex and prone to metastasis and relapse, so novel diagnostic biomarkers and therapeutic strategies are urgently needed. As nanoscale vesicles secreted by cells, exosomes carry bioactive molecules, including nucleic acids, proteins, and lipids, and play a key role in regulating the tumor microenvironment (TME), forming the pre-metastatic niche (PMN) and contributing to drug resistance in CRC. Through bibliometrics, this study reviewed research progress, cooperation networks, and frontiers of exosomes in the field of CRC to fill the gap of systematic analysis and provide a theoretical basis for future research. Methods Based on the Web of Science Core Collection (WOSCC) database, the relevant literature on exosomes in the field of CRC from 2003 to 2024 was searched. Tools such as CiteSpace, VOSviewer, RStudio, GraphPad, and SciExplorer are used to visually analyze publishing trends, national contribution, institutional cooperation, author influence, journal distribution, co-citation network, and keyword co-occurrence to predict future research hotspots. Results This study included 1705 articles from 76 countries, involving 9113 authors and 2240 institutions, and published in 513 journals. The analysis showed that the research on exosomes in CRC showed a continuous upward trend, especially in recent years, indicating that this field has received more and more attention and in-depth research. China leads the world in terms of research output (> 50%), but the number of citations per article is relatively low, while the United States stands out regarding citation impact and academic centrality. China's domestic academic cooperation is relatively active, but international cooperation must be strengthened. Cancers is the most widely published journal in the field. Simpson R.J. tops the list of authors with 16 papers, and Thery C. is the most frequently cited author. In addition to "colorectal cancer" and "extracellular vesicles," "metastasis," "biomarker," and "progression" are also popular keywords. It reflects that the research mainly focuses on the role of exosomes in the occurrence, development, diagnosis, prognosis, and treatment of CRC. Emerging research trends are gradually shifting from basic biological mechanisms to clinical applications and technological innovations, emphasizing the potential value of exosomes in the early diagnosis of CRC, therapeutic monitoring, and individualized therapy. Conclusion Through bibliometric analysis, this study reviewed the current research status and development trend of exosomes in CRC. Future studies should focus on strengthening international cooperation to promote the effective transformation of basic research into clinical application to achieve breakthroughs in CRC precision medicine. colorectal cancer exosome bibliometric analysis visualization R-bibliometrix research trends Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 1 Introduction CRC is the third most common malignant tumor in the world and the second largest cause of cancer-related death, with more than 1.9 million new cases and approximately 930,000 deaths every year [ 1 ] . Although the popularization of screening techniques (such as colonoscopy and fecal DNA testing) and the use of targeted therapies (anti-EGFR /VEGF therapy) have significantly improved clinical management [ 2 ] , the prognosis of CRC is still not optimistic, and recurrence and metastasis are still the leading causes of treatment failure. Therefore, it is crucial to deeply understand CRC pathogenesis and development and search for new diagnostic biomarkers and therapeutic targets. In recent years, exosomes have received extensive attention as an essential medium of intercellular communication. Such nanoscale vesicles with a 30-150nm diameter are released by the fusion of intracellular polyvesicles with cell membranes. They carry abundant bioactive molecules, including nucleic acids, proteins, and lipids, which can participate in tumors' occurrence, development, metastasis, and drug resistance by regulating gene expressions, signaling pathways, and immune response of target cells [ 3 , 4 ] . There is increasing evidence that exosomes play an important and complex role in the occurrence and progression of CRC. On the one hand, exosomes released by tumor cells can promote the proliferation, invasion, and metastasis of tumor cells and inhibit the function of immune cells, thus promoting the development of tumors. On the other hand, some exosomes may play a role in tumor suppression, for example, by delivering tumor suppressor genes or activating immune responses [ 5 ] . In addition, exosomes are also considered potential diagnostic markers for early diagnosis and prognosis assessment of CRC. Although the exploration of exosomes in CRC research continues to deepen, the existing review literature usually lacks systematic analysis of research trends, international cooperation models, and the evolution of hotspots, and the current bibliometric analysis of CRC exosomes is still blank. Based on the WOSCC database and combined with tools such as CiteSpace, VOSviewer, and RStudio, this study conducted a multi-dimensional comprehensive analysis of the literature in this field over the past 20 years. The purpose of this study is to (1) reveal the knowledge structure and evolution of this field; (2) identify collaboration networks of key authors, institutions, and countries; (3) predict future research directions and discuss current challenges and opportunities. The study results will provide a data-driven decision-making basis for scholars in related fields and promote the application of exosomes in the clinical transformation of CRC. 2 Materials and methods 2.1 Data source The data for this study was sourced from the WOSCC database, a widely recognized and comprehensive multidisciplinary journal citation database known for its extensive literature coverage and high-quality citation indexes. Each record in the WOSCC database includes metadata such as publication year, author information, institutional affiliation, document type, research field, journal title, citation counts, and reference lists. This rich data set provides researchers with valuable resources, enabling in-depth analysis of citation patterns and research trends in academic literature. Therefore, the WOSCC database is considered an ideal choice for bibliometric analysis, helping to track the development of scholarly research and reveal knowledge flow and educational influence across different disciplines. 2.2 Search strategy We systematically searched and compiled relevant publications on exosomes in CRC from January 1, 2003, to December 21, 2024. The inclusion criteria were as follows: (1) full-text publications related to exosomes in CRC, (2) articles and reviews written in English. The exclusion criteria included: (1) publications unrelated to exosomes in CRC; (2) certain document types, including proceedings papers, meeting abstracts, editorial materials, early access articles, letters, retracted publications, book chapters, and corrections. The search was performed on a single day to ensure consistency in data collection. Data were exported in the format of “full records and cited references” as plain text, as shown in Fig. 1 , which outlines the screening process. The search formula used was as follows: (((((((((((((((((TS=("Colorectal Neoplasms")) OR TS=("Colorectal Neoplasm")) OR TS=("Neoplasm, Colorectal")) OR TS=("Neoplasms, Colorectal")) OR TS=("Colorectal Tumors")) OR TS=("Colorectal Tumor")) OR TS=("Tumor, Colorectal")) OR TS=("Tumors, Colorectal")) OR TS=("Colorectal Cancer")) OR TS=("Cancer, Colorectal")) OR TS=("Cancers, Colorectal")) OR TS=("Colorectal Cancers")) OR TS=("Colorectal Carcinoma")) OR TS=("Carcinoma, Colorectal")) OR TS=("Carcinomas, Colorectal")) OR TS=("Colorectal Carcinomas")) OR TS=(CRC) AND (((((TS=(exosomes)) OR TS=(exosome)) OR TS=("extracellular vesicle")) OR TS=("extracellular vesicles")) OR TS=(exosomal)) OR TS=("extracellular vesicle"). A bibliometric analysis was conducted on the collected publications for data evaluation and visualization. Two researchers independently analyzed and cross-verified the data to ensure accuracy and reliability. 2.3 Data analysis This study employed many data analysis approaches, integrating quantitative and qualitative techniques to examine research trends, collaborations, and knowledge structures. Quantitative analysis focused on annual publication counts, rankings of top contributors (countries, institutions, authors, and journals), and temporal trends in research output. Qualitative analysis explored intellectual networks through co-citation and collaboration network analysis, identifying relationships among authors, journals, and references. Advanced bibliometric tools were utilized: CiteSpace (version 6.2.R4) for co-citation, co-word, and keyword analysis to visualize research hotspots and frontiers; VOSviewer (version 1.6.18) for constructing and clustering bibliometric networks; RStudio (bibliometrix package) for thematic evolution and research structure analysis; and GraphPad (version 8.0.2) and SciExplorer for data visualization and statistical analysis. This multi-tool approach ensured a comprehensive examination of the research landscape, providing insights into publication trends, collaborative networks, and emerging research directions over the past two decades. 3 Results 3.1 Global trend of publications A total of 1,705 publications related to exosomes in CRC were retrieved from the WOSCC database, comprising 1,103 original research articles (65%) and 602 review articles (35%). These publications originated from 76 countries/regions, involving 2,240 institutions and 9,113 authors. Figure 2 illustrates the annual publication volume and its developmental trajectory. The x-axis represents the years, while the left and right y-axes indicate the annual publication count and cumulative publication volume, respectively. The light blue bars denote the annual publication count, and the blue curve represents the cumulative publication volume. The data reveal a significant increase in yearly publications since 2003, which can be categorized into three distinct phases. In the initial phase (2003–2013), the annual publication count remained below 10, indicating that exosome research in CRC was nascent and had not yet garnered widespread attention. The second phase (2014–2020) witnessed a substantial increase in publications, marking a period of rapid development. During this phase, researchers began to recognize the potential of this field, leading to a surge in academic interest and a proliferation of research outputs. In the third phase (post-2020), the field has continued to attract significant attention, with an annual publication volume exceeding 260 articles. Exosome research has become a prominent focus in CRC, consistently attracting experts and scholars for in-depth exploration and driving innovative outcomes. 3.2 Analysis of countries/regions As of December 2024, a total of 76 countries and regions worldwide have conducted research on exosomes in CRC (Fig. 3 A). Among the top ten countries/regions by publication volume (Fig. 3 B, Table 1 ), China contributes over 50% of the global output, and its cumulative citation count has reached 33,570, far surpassing other countries/regions. However, China ranks lower in terms of the average citations per paper (37.51), indicating that the overall quality of its research is relatively lower. The United States ranks second with 221 publications and 13,017 cumulative citations, while its centrality score of 0.4 places it at the top among all countries/regions. We further analyzed the collaboration networks among countries (Fig. 3 C) and the countries of corresponding authors (Fig. 3 D). In this context, "multinational publications(MCP)" refer to papers co-authored by researchers from different countries, while "single-country publications(SCP)" are those authored by researchers from the same country. The results show that China and the United States have a relatively close collaboration, whereas academic cooperation within most countries primarily occurs domestically, with limited international academic exchange and collaboration. Notably, MCPs constitute less than one-fifth of the total publications. 3.3 Analysis of institutions A total of 2,240 institutions have systematically published research on exosomes in CRC. The top ten institutions by publication volume are all located in China (Table 2 ). Fudan University leads in publication count (57), total citations (3,639), and average citations per paper (63.84). The collaboration network among institutions is depicted in Fig. 4 , where arcs of different colors represent collaborative relationships, with thicker lines indicating stronger collaborations. Shanghai Jiao Tong University and Fudan University exhibit the most extensive and robust collaborations, primarily with institutions such as Tongji University, Shanghai University of Traditional Chinese Medicine, Zhejiang University, and Nanjing Medical University, which are predominantly located in coastal regions. Therefore, we advocate for enhanced inter-regional institutional collaborations to break down academic barriers. 3.4 Analysis of journals and co-cited journals This study comprehensively analyzed the top ten productive journals and co-cited journals based on publication volume, citation counts, impact factor (IF), and journal quartiles. According to publication volume (Table 3 ), Cancers leads with 68 publications, followed by the International Journal of Molecular Sciences (63) and Frontiers in Oncology (61). This aligns with the journal publication density map in Fig. 5 A. Among these high-output journals, Molecular Cancer boasts the highest IF of 27.7, highlighting its leading position in oncology and related fields. The academic influence of journals is often assessed by their co-citation frequency. Journals with high co-citation counts typically wield significant impact in the academic community, playing a crucial role in advancing scientific research. Based on Fig. 5 B and Table 3 , the most co-cited journals are Cancer Research (1,076), PLOS ONE (1,047), and Nature (965). Notably, Nature ranks high in co-citation counts and has the highest IF among the top ten co-cited journals at 50.5. Furthermore, 90% of these co-cited journals are in the Q1 quartile, underscoring their high impact and authority in the academic field. Figure 5 C illustrates the distribution of journals and the relationships between citing and cited journals through a dual overlay map, highlighting the thematic distribution of academic publications in this field. The left and right sides represent citing and cited journals, respectively, with colored lines indicating citation links, where thicker lines denote stronger connections. Two primary citation pathways are identified: research published in journals within the molecular/biology/genetics domain is predominantly cited by journals in the molecular/biology/immunology and medicine/medical/clinical domains. 3.5 Analysis of authors and co-cited authors In this study, 9,113 authors contributed to publishing all research outcomes. Among them, 146 authors had more than 50 co-citations, indicating their significant academic influence. Table 4 lists the top ten authors by publication volume, who collectively contributed 120 papers, accounting for 7% of the related papers in the field. Specifically, Simpson R.J. ranks first with 16 published papers, followed by Greening D.W. (14), Wang C. (14), Du L. (13), and Li J. (12). To provide a more precise representation of the collaborative network and academic influence among these scholars, we utilized CiteSpace software for a visual analysis of the author network, as shown in Fig. 6 A. When the works of two or more authors are cited together within the same reference list of one or more papers, these authors are said to have a co-citation relationship or are called co-cited authors. As shown in Table 4 , the top ten co-cited authors have been cited over 2,500 times collectively. Figure 6 B presents the co-citation network visualization, where each node represents an author, and the node size corresponds to the citation frequency. In the co-citation network, Thery C. has the highest citation count (358), followed by Kalluri R. (331) and Zhang Y. (286). The widespread citation of these authors’ works reflects their profound impact and academic standing in the field. 3.6 Analysis of co-cited references and reference burst We conducted a visual analysis of co-cited references from 2003 to 2024 using CiteSpace, resulting in a network consisting of 1,127 nodes and 5,638 links (Fig. 7 A). Table 5 lists the top ten most co-cited references related to exosomes in CRC. The three most frequently cited papers are: Kalluri R. et al., 2021, Science 3 ; Hu J.L. et al., 2019, Molecular Cancer [ 6 ] ; and Welsh J.A. et al., 2024, Journal of Extracellular Vesicles [ 7 ] . Notably, Kalluri R. and colleagues’ seminal review, "The biology, function, and biomedical applications of exosomes," published in Science, has been pivotal in advancing exosome research. This comprehensive review outlines the fundamental concepts, biological characteristics, and potential clinical applications of exosomes, laying a solid foundation for subsequent research. Among these influential papers, three focus primarily on the fundamental biological functions of exosomes, including their roles in cellular communication, secretory pathways, and cellular uptake, representing key foundational work in the exosome field. Six papers emphasize the specific roles of exosomes in CRC, particularly their involvement in tumor progression, metastasis, chemotherapy resistance, and modulation of the TME. One paper addresses the need for standardization in exosome research, promoting methodological advancements in the field. Cluster analysis of co-cited references (Fig. 7 B) and the temporal evolution of co-citation clusters (Fig. 7 C) reveal distinct research trends. Early hotspots included tumor-associated antigens (cluster 7), promoter assays (cluster 11), and CCA (cluster 15). Mid-term hotspots encompassed the secretome (cluster 5), CRMP-2 (cluster 9), blood-brain barrier (cluster 10), sunitinib (cluster 13), and circRHOBTB3 (cluster 16). Current popular research directions focus on CRC (cluster 0), microsatellite instability (cluster 1), fibroblasts (cluster 3), circRNA (cluster 5), liquid biopsy (cluster 6), hypoxia (cluster 8), targeted therapy (cluster 12), and circulating tumor cells (cluster 14). Additionally, we identified the top 50 references with the most strongest citation bursts in the field, as shown in Fig. 7 D. Early references typically exhibited higher citation intensity, likely due to their pioneering nature, primarily focusing on exosome discovery and fundamental functions. While later references continued to garner significant citations, there was a slight decline in intensity compared to earlier works, likely reflecting the broadening of the field and the emergence of new research areas. These later studies primarily focus on the clinical applications of exosomes in CRC diagnosis, prognosis, and treatment. The paper with the highest citation burst intensity is by Hoshino A. [ 8 ] , published in Nature in 2015, with an intensity of 35.13. Known for its groundbreaking nature, this study explores the critical roles of exosomes in tumor metastasis, immune evasion, and drug resistance, leading to widespread citations in subsequent research. Following closely are works by Ogata-Kawata H. (PLOS ONE, 2014) with an intensity of 33.42, and Matsumura T. (British Journal of Cancer, 2015) with an intensity of 30.12. These studies are considered seminal and have significantly influenced subsequent research. Notably, as of 2024, six studies closely related to this field continue to experience citation bursts, with the most notable being the work by Sung H. et al., published in 2021, which has maintained a high citation rate since its publication. 3.7 Analysis of keywords and keywords burst In the study of the application of exosomes in CRC, keyword clustering analysis has been used to identify different research themes and development trends. According to the co-occurrence analysis of keywords in VOSviewer, in addition to "colorectal cancer" (637) and "extracellular vesicles" (509), other popular keywords include "metastasis" (279), "biomarkers" (193), and "progression" (153) (Table 6 , Fig. 8 A and 8 B). By removing irrelevant keywords and constructing a network containing 165 keywords that appear at least 15 times, five distinct research clusters were identified. The first cluster of keywords (purple) primarily focuses on the detection of biomarkers in exosomes using liquid biopsy technology for the diagnosis, prognostic evaluation, and recurrence monitoring of CRC. Core keywords include "liquid biopsy," "biomarkers," "diagnostic biomarkers," "prognostic biomarker," "prognostic value," "cell-free DNA," "microRNAs," etc. The emphasis is on the clinical application of liquid biopsy and the clinical significance of these biomarkers. The second cluster of keywords (yellow) involves tumor cells' proliferation, invasion, and metastasis and the regulatory role of non-coding RNAs (such as circRNA and lncRNA) in these processes. Keywords such as "epithelial-mesenchymal transition (EMT)," "long noncoding RNA," "circRNA," "cell proliferation," "tumorigenesis," "invasion," "migration," "hepatocellular carcinoma," etc., indicate that the research mainly focuses on the biological behaviors of tumor cells and their molecular mechanisms, with a particular emphasis on the role of non-coding RNAs in tumor initiation and progression. The third cluster of keywords (blue) centers around exosome biosynthesis, secretion, composition, and intercellular communication roles. Keywords like "exosome," "biogenesis," "intercellular communication," "proteomics," "vesicles," "mass spectrometry," etc., focus on the biological characteristics of exosomes and their role in intercellular communication. The fourth cluster of keywords (green) explores the role of exosomes in remodeling the TME and in multidrug resistance. Keywords such as "extracellular vesicles," "cancer stem cells," "cancer-associated fibroblasts (CAFs)," "tumor microenvironment," "drug resistance," "immunotherapy," "delivery," and "nanoparticles" mainly discuss the complexity of the TME and its impact on treatment responses, particularly in terms of drug resistance and potential immunotherapy targets. The fifth cluster of keywords (red) focuses on the progression, metastasis mechanisms, and potential therapeutic targets in CRC. Keywords such as "colorectal cancer," "metastasis," "expression," "progression," "inflammation," "angiogenesis," and "macrophages" indicate that the research aims to reveal the biological mechanisms of CRC and explore new therapeutic targets to improve patient prognosis. 3.8 Research trends evolution We performed a visual analysis of the key trends and topics related to exosomes in CRC over the past fifteen years using RStudio (Fig. 9 ). The study revealed a rising frequency of keywords such as "tumor-associated macrophages (TAMs)," "polarization," "promotes metastasis," and "progression," indicating that exosome-mediated remodeling of the TME has gradually become a research focus in this field, particularly in its roles in promoting tumor metastasis and immune evasion. Additionally, the increasing frequency of keywords like "biomarkers," "diagnostic biomarkers," "circulating microRNAs," "serum," and "plasma" reflects growing attention to the identification of clinically relevant biomarkers from exosomes. Notably, exosomes have demonstrated substantial potential not only in tumor biomarker discovery and microenvironment regulation but also as therapeutic tools, particularly in drug delivery. Although the keywords directly related to therapy remain relatively limited in current research, the potential of engineered exosomes as drug carriers is becoming more apparent. Overall, the research focus is progressively shifting from basic biological mechanisms to clinical applications and technological innovations, playing a significant role in early diagnosis, treatment monitoring, and personalized therapy. 4 Discussion 4.1 General information Over the past two decades, there has been a significant increase in publications on exosomes in CRC, highlighting the potential of this field in oncology research. Through bibliometric analysis, this paper reveals the evolution of research in this field: from the initial exploratory phase (2003–2013) to the period of rapid innovation (2014–2020) and finally to the surge in scientific research (after 2020). This development trajectory reflects the growing recognition within the academic community of the central role of exosomes in CRC initiation and progression, as well as their dual value as diagnostic and prognostic biomarkers and therapeutic targets. China has made the most considerable contribution in this area, accounting for over 50% of global research output. However, the relatively low average citation count per article suggests that the quality and impact of research in the country still have room for improvement. Collaboration network analysis indicates that while domestic academic collaborations in China are relatively strong, international collaborations remain limited. This highlights the importance of strengthening international and cross-institutional collaborations to enhance the global impact of exosome research further. Notably, high-impact papers are predominantly published in Q1 journals, and foundational works by scholars such as Thery C. and Kalluri R. occupy central positions in the citation network, indicating the field's reliance on the interdisciplinary integration of molecular biology and clinical oncology. Overall, these trends suggest that the role of exosomes in CRC research is steadily maturing, driving the exploration of new diagnostic and therapeutic approaches in the field. 4.2 Citation bursts Citation explosion refers to the phenomenon where literature is frequently cited over a short period, reflecting the emergence of research hotspots and shifts in scholarly focus. Analyzing highly cited literature allows for effectively tracking emerging issues and development trends related to exosomes in CRC. Early research (2012–2017) primarily focused on the fundamental biological functions of exosomes and their roles in cancer progression, thereby laying the foundation for exosome research. Mid-term research (2017–2020) increasingly focused on the clinical applications of exosomes, particularly their potential as diagnostic biomarkers and therapeutic targets, thus facilitating the clinical translation of related technologies. Recent studies (2020–2024) have further explored the molecular mechanisms of exosomes in CRC and their clinical applications. Notably, six papers closely related to the theme are currently experiencing citation bursts. A detailed analysis of these papers reveals the current hot topics in exosomes in CRC: (1) Exosomal non-coding RNAs and CRC progression: three of the six papers undergoing bursts are related to this topic. Shang AQ et al. [ 9 ] indicated that exosomal circPACRGL promotes CRC via the miR-142-3p/miR-506-3p-TGF-β1 axis; Wang XY et al. [ 10 ] demonstrated that exosome-delivered circRNAs promote glycolysis through the miR-122-PKM2 axis, which in turn induces CRC drug resistance; Zhao SL et al. [ 11 ] found that tumor-derived exosome miR-934 induced macrophage M2 polarization and promoted CRC liver metastasis. Consequently, regulating CRC progression by exosomal non-coding RNAs has become a significant focus of current research. Non-coding RNAs, such as circRNAs and miRNAs, regulate tumor cell proliferation, metastasis, and drug resistance through interactions with intracellular molecules. Investigating the mechanisms underlying the action of these molecules can deepen our understanding of CRC pathogenesis and provide theoretical support for the development of novel diagnostic biomarkers and therapeutic targets. (2) Application of exosomes as biomarkers: the potential of exosomes as biomarkers has been emphasized in studies by Kalluri R et al. 3 and Hoshino A et al. [ 12 ] . Kalluri R et al. comprehensively elaborated on the biological properties and functions of exosomes, establishing a foundation for further research on their role in CRC. They also pointed out that proteins and nucleic acids carried by exosomes can reflect tumor characteristics and serve as potential biomarkers. Hoshino A et al. expanded the application of exosomes as biomarkers across various cancers, offering a systematic approach to discovering CRC-specific biomarkers. Both studies emphasize the importance of exosomes as a liquid biopsy, foreseeing their promising applications in CRC diagnosis, prognostic assessment, and therapeutic monitoring, which may provide a basis for personalized treatment. (3) Exosomes regulate the TME: Zhao SL et al. 11 found that exosomes secreted by CRC cells are enriched in miR-934, which targets and inhibits pro-inflammatory factor expression, induces macrophage polarization to the M2 type, and upregulates M2 markers (e.g., CD206 and Arg1). Animal experiments demonstrated that the injection of miR-934-containing exosomes significantly increased the incidence of liver metastasis. This study demonstrated that exosomes play a crucial role in regulating the TME, offering new insights into the metastatic mechanisms of CRC and potential targets for future therapeutic strategies. (4) Drug delivery and drug resistance reversal by exosomes: tumor drug resistance remains a significant challenge in treating CRC. As natural nanovesicles with favorable biocompatibility and targeting capabilities, exosomes can be engineered to serve as drug-delivery vehicles. When therapeutic molecules (e.g., miRNA inhibitors and chemotherapeutic agents) are loaded into exosomes, these nanoparticles can be accurately delivered to tumor cells, thereby overcoming drug resistance and enhancing therapeutic efficacy. Liang GF et al. [ 13 ] proposed an engineered exosome-targeted co-delivery system that combines miR-21 inhibitors and chemotherapeutic agents to reverse drug resistance in CRC. This innovative strategy offers novel approaches for overcoming tumor drug resistance. In summary, research on exosomes in CRC is advancing, encompassing various aspects, from molecular mechanisms to clinical applications. As research progresses, the potential of exosomes in diagnosis, therapy, and drug delivery will be increasingly realized. 4.3 Research hotspots 4.3.1 The role of exosomes in the development of CRC (1) Exosomes' immunomodulatory effects on the TME of CRC Exosomes play a dual role in the immune regulation of the TME in CRC. By mediating interactions between tumor cells and immune cells, stromal cells, and non-cellular components, exosomes can both promote immune escape and activate immune responses, profoundly affecting the progression of the tumor [ 14 ] . In terms of immunosuppression, exosomes can transfer bioactive molecules between different cell types in the TME, helping tumor cells evade immune surveillance and induce immune tolerance, ultimately promoting cancer progression [ 15 ] . For example, exosomes derived from CRC carry tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which directly induces apoptosis of CD8⁺ T cells by binding to the surface receptors of T cells, thereby suppressing the immune response [ 16 ] . Exosomes secreted by CRC cells are rich in TGF-β1, which activates the TGF-β/Smad signaling pathway, upregulates the expression of Treg marker genes such as FoxP3 and CTLA-4, and induces Treg proliferation [ 17 ] . CRC exosomes can also alter the differentiation direction of monocytes, promoting their transformation into myeloid-derived suppressor cells (MDSCs) and inhibiting the proliferation of immune cells and T cells 13 . CRC exosomes can also alter the differentiation direction of monocytes, promoting their transformation into MDSCs, thereby inhibiting the proliferation of immune cells and T cells [ 18 ] . Feng et al. demonstrate that CRC exosomes inhibit the NLRP3 pathway through TUT7-mediated accumulation of miR-1246, promoting the differentiation of M2-type TAMs, thereby enhancing the immunosuppressive environment [ 19 ] . Furthermore, CAFs transmit signals through exosomes and mediate the proteasomal degradation of MOB1A via the overexpression of WEE2-AS1, inhibiting the Hippo pathway and promoting the proliferation of CRC. In turn, tumor cells can reactivate CAFs, forming a self-sustaining pro-cancer environment [ 20 ] . In CRC exosomes, circPACRGL regulates the TGF-βsignaling pathway through miR-142-3p/miR-506-3p, inducing the transformation of tumor-associated neutrophils from anti-tumor (N1) to pro-tumor (N2) phenotypes, thereby promoting the proliferation and metastasis of CRC cells 9 . However, exosomes not only exert immunosuppressive effects but can also activate immune responses, inhibiting tumor growth and metastasis. For instance, exosomes secreted by CRC cells contain miR-424, which can hinder the CD28-CD80/86 costimulatory pathway, activate immune checkpoints, and enhance immune responses, ultimately suppressing tumor growth [ 21 ] . 2. The role of exosomes in the metastasis and invasion of CRC 1 Exosomes mediate angiogenesis in CRC Angiogenesis is the core event of tumor occurrence, progression, and metastasis. It promotes tumor growth by providing oxygen and nutrients and releasing pro-angiogenesis factors. Exosomes are closely related to angiogenesis and can promote the proliferation of CRC cells by regulating angiogenesis. Studies have shown that miRNA components, such as miR-21-5p, significantly enhance vascular permeability and neovascular density by inhibiting KRIT1 expression in endothelial cells, activating the β-catenin signaling pathway, and promoting the expression of VEGFA and CCND1 [ 22 ] . Meanwhile, miR-1246 induced tubular differentiation of endothelial cells by activating the Smad1/5/8 pathway [ 23 ] . However, miR-320d further improves angiogenesis efficiency by inhibiting GNAI1 and activating the JAK2/STAT3 cascade. In addition, circRNAs [ 24 ] , such as circTUBGCP4, activate the AKT signaling pathway by inhibiting miR-146b-3p, promoting the formation of vascular endothelial cells and tumor metastasis [ 25 ] . CircPACRGL acts as a sponge for miR-142-3p and miR-506-3p, enhancing TGF-β1 expression by inhibiting the activity of these miRNAs, thereby promoting angiogenesis. In addition to non-coding RNAs, exosomes derived from CRC cells are enriched with proteins that promote angiogenesis. Exosomes were found to increase the expression of integrin (ITG) β1 and VEGFA in human umbilical vein endothelial cells, which are essential for blood vessel growth, maturation, and endothelial sprout formation25. In addition, B7-H3 has been identified as an integral component of CRC exosomes, promoting tumor angiogenesis and metastasis by activating the AKT1/mTOR/VEGFA signaling pathway [ 25 , 26 ] . Exosomes also fine-tune the blood vessel morphogenesis and angiogenesis process by influencing tip cell formation. These findings highlight the key role of exosomes in regulating tumor angiogenesis and provide a theoretical basis for developing novel anti-angiogenic therapeutic strategies targeting exosomes. 2 Exosomes promote EMT in CRC EMT is a core biological process in CRC metastasis, characterized by the down-regulation of epithelial markers (such as E-cadherin) and up-regulation of mesenchymal markers (such as N-cadherin and vimentin). It was accompanied by a loss of cell polarity and increased aggressiveness. Exosomes induce EMT by delivering functional RNAs and proteins, significantly enhancing the migration and metastasis ability of CRC cells. Studies have shown that the CRC-derived exosome miR-106b-3p targets the tumor suppressor gene DLC-1, activates the EMT program, and promotes lung metastasis [ 27 ] . Similarly, exosome miR-335-5p significantly enhances migration in both in vitro and in vivo models by inhibiting RASA1 expression, activating the RAS signaling pathway, and inducing EMT phenotype [ 28 ] . In addition, non-coding RNAs play a key role in exosome-mediated EMT. For instance, exosomal lncRNA 91H remodels the actin network and enhances CRC cell migration by binding to the cytoskeletal regulatory protein ARPC5 [ 29 ] . CircCSPP1 acts as a competitive endogenous RNA that binds to miRNA and promotes COL1A1 expression, thereby promoting EMT and liver metastasis in CRC cells [ 30 ] . At the protein regulatory level, exosomal ADAM17 accelerates EMT-related metastasis by cutting the extracellular domain of E-cadherin, destroying intercellular adhesion connections [ 31 ] . In addition, exosomes indirectly regulate EMT processes by remodeling the TME. Studies have demonstrated that exosomes can induce M2 macrophage polarization, activate the PI3K/AKT signaling pathway, and synergically promote EMT and angiogenesis, thus forming a positive feedback loop that facilitates metastasis [ 11 ] . As a core regulator of the TME, exosomal LINC00355 secreted by CAFs releases adaptor proteins through competitive binding to miR-34b-5p, thereby enhancing chemotherapy resistance and accelerating the EMT process [ 32 ] . Moreover, hypoxic conditions within the TME stimulate CRC cells to release exosomes rich in Alu RNA, which activate the NLRP3 inflammasome, promote IL-1β secretion, and drive the expression of EMT-related genes via an NF-κB-dependent mechanism, creating a pro-metastatic inflammatory cascade [ 33 ] . 3 Exosomes promote the formation of PMN and organ metastasis in CRC Exosomes play a key role in the formation of PMN and organ metastasis of CRC. First, exosomes drive metastasis targeting through ITG-mediated organotaxis. Hoshino A et al. revealed that ITGα6β4 and ITGα6β1 were mainly present in pulmonary exosomes, while ITGαvβ5 was primarily present in hepatic exosomes. ITG activates fibroblasts through the nuclear factor κB signaling pathway and induces high levels of pro-inflammatory cytokine production, triggering PMN establishment in the liver and lungs [ 8 , 34 ] . Second, exosomes reshape the microenvironment of the target organ through their contents. For example, miR-25-3p facilitates the metastasis of CRC cells by inhibiting KLF2/KLF4 in endothelial cells, reducing the expression of tight junction proteins(such as ZO-1 and occludin) and increasing vascular permeability [ 35 ] . In addition, the B7-H3 protein carried by exosomes activates the AKT1/mTOR/VEGFA signaling pathway, promoting angiogenesis and providing nutritional support for metastasis [ 26 ] . In terms of immune regulation, CRC-derived exosomes deliver miR-372-5p and miR-106b, inducing M2 macrophage polarization, promoting CXCL12 secretion, and activating the WNT/β-catenin pathway, thereby establishing an immunosuppressive microenvironment that supports tumor metastasis [ 36 , 37 ] . In addition, exosomes also provide conditions for tumor cell invasion by degrading the extracellular matrix (ECM) of the target organ. Exosomal lncRNAs carried by exosomes promote fibroblast activation and ECM remodeling by activating TGF-β and other pathways to form loose matrix structures [ 38 ] . In summary, exosomes coordinate the formation of PMN through multiple mechanisms, such as organ-specific targeting, angiogenesis, immune regulation, and ECM remodeling, providing the "soil" for CRC metastasis and ultimately promoting the organ metastasis of CRC. 4.3.2 The application of exosomes in the diagnosis and prognosis of CRC (1)Exosomal miRNAs Exosomal miRNAs show essential value in the early diagnosis and prognosis assessment of CRC. Studies indicate that miR-21 is significantly up-regulated in the serum exosomes of CRC patients and promotes tumor proliferation by inhibiting PDCD4 and other tumor suppressor genes [ 39 ] , with a diagnostic sensitivity of 75% and specificity of 84% [ 40 ] . Han et al. [ 41 ] also observed that miR-15b, miR-16, and miR-31 were notably up-regulated in the exosomes of CRC patients, and the combination of these miRNAs could significantly improve the accuracy of CRC diagnosis. MiRNAs such as miR-150-5p, miR-335-5p, miR-17-92, and miR-215 are closely associated with CRC invasion and metastasis, making them potential biomarkers [ 28 ] . Among these, the low expression of miR-150-5p correlates significantly with poor tumor differentiation, lymph node metastasis (LNM), and advanced TNM stage. The expression of miR-150-5p in CRC patients with LNM is approximately 2.4 times lower than in non-metastatic patients. However, after surgical resection of the tumor, the serum levels of miR-150-5p significantly increase, making it a valuable indicator for prognosis assessment and postoperative monitoring [ 42 , 43 ] . Another study found that low miR-193a and high let-7g expression patterns were strongly associated with shorter overall survival in CRC patients, suggesting their potential as biomarkers for relapse monitoring [ 44 ] . Furthermore, exosomal miRNAs also reflect chemotherapy sensitivity. For instance, the expression levels of miR-92a-3p and miR-221-3p are significantly correlated with oxaliplatin resistance, with the AUC of predicted efficacy being 0.735 and 0.774, respectively [ 45 ] . (2)Exosomal proteins Exosomal proteins have also proven to be valuable biomarkers for CRC. Studies reveal that the expression levels of exosomal proteins in the blood of CRC patients are markedly different from those in healthy controls. Proteins such as CD147, HSP60, and GPC1 in exosomes can serve as early diagnostic biomarkers for CRC. The expression of exosomal proteins is significantly increased in metastatic CRC patients, with these levels closely linked to tumor aggressiveness and metastatic potential. Sun et al. [ 46 ] found that exosomal CPNE3 levels were significantly elevated in patients with advanced TNM stage or distant metastasis. The combined detection of exosomal CEA and CPNE3 showed a sensitivity of 81.2% and specificity of 84.8%, significantly outperforming single detections of either CEA or CPNE3. Moreover, patients with high CPNE3 expression exhibited lower disease-free survival and overall survival rates compared to those with low CPNE3 expression, highlighting the potential of CPNE3 as a biomarker for early diagnosis and prognosis assessment. Additionally, exosomal PD-L1 promotes immune escape by inhibiting T-cell activity, suggesting its use as a biomarker for poor prognosis. Variations in PD-L1 levels after surgery or chemotherapy can also help monitor the risk of recurrence [ 47 ] . (3)Exosomal lncRNAs Exosomal lncRNAs are tissue-specific and exhibit stable expression across various tissues. Studies have demonstrated that lncRNA CRNDE-h is significantly upregulated in serum exosomes of CRC patients, and its diagnostic value surpasses that of the traditional biomarker CEA. When combined with CEA, the diagnostic efficiency improves, with an AUC of 0.91 [ 48 ] . lncRNA-ADAMTS9-AS1, an antisense lncRNA, is dysregulated in multiple tumors and inhibits CRC progression by interfering with the Wnt/β-catenin signaling pathway, making it a potential diagnostic biomarker [ 49 ] . Furthermore, the overexpression of lncRNA CRNDE-h is positively associated with LNM and distant metastasis in CRC, suggesting its value in prognosis evaluation 48 . Another example is lncRNA PCGEM1, which is significantly upregulated in CRC. When combined with miR-152-3p, it has been shown to improve diagnostic accuracy, suggesting its potential as a novel biomarker for prognostic evaluation [ 50 ] . (4)Exosomal circRNAs CircRNAs possess a covalent closed-loop structure, making them stable and highly conserved. They are abundantly expressed in eukaryotic tissue development, and the expression profiles of circRNAs in exosomes from tumor patients differ significantly from those in healthy individuals. Their high abundance, specificity, and stability make them promising non-invasive biomarkers for liquid biopsy. For instance, circRNA-0004771 is significantly upregulated in the serum exosomes of CRC patients, with an AUC of 0.88 for distinguishing CRC from healthy controls and 0.816 for distinguishing stage I and II patients from other benign intestinal diseases [ 51 ] . This shows better diagnostic sensitivity and specificity than traditional biomarkers. CircRNAs also promote metastasis by mediating communication between tumor cells and the TME. For example, exosomal circ-0084043 secreted by CAFs activates endothelial cells to promote angiogenesis through the miR-153-5p/SNAI1 axis, which is linked to CRC liver metastasis [ 52 ] . Circ-FMN2 is overexpressed in the serum and exosomes of CRC patients, and its levels correlate positively with the LNM and TNM stages. Circ-FMN2 accelerates CRC cell proliferation and metastasis while inhibiting apoptosis through the miR-338-3p/MSI1 axis, making it a potential specific biomarker for CRC and a therapeutic target for clinical applications [ 53 ] . Furthermore, exosomal circRNAs are involved in the mechanism of chemotherapy resistance. For example, the high expression of circ-0004771 in CRC patients is associated with oxaliplatin resistance, with its levels predicting treatment response and survival outcomes [ 54 ] . 4.3.3 The application of exosomes in the treatment of CRC (1) Drug delivery Exosomes, as natural nanocarriers, have significant advantages in CRC drug delivery. Their lipid bilayer structure and inherent biocompatibility enable efficient passage across physiological barriers, such as gastrointestinal mucosa and vascular endothelium, allowing targeted drug delivery to specific sites. Studies have demonstrated that exosomes derived from mesenchymal stem cells retain structural stability by carrying transmembrane proteins (e.g., CD9 and CD63), which protect the drugs from degradation within the circulatory system, thus enhancing delivery efficiency [ 55 ] . Furthermore, exosomes can cross the blood-brain barrier, holding promise for targeted treatment of CRC metastases in the brain. To improve their targeting specificity, exosomes can also be engineered through chemical modifications or gene-editing techniques. For instance, modifying ligands of tumor-associated antigens (such as CEA or EpCAM) on the surface of exosomes enables them to target and accumulate on CRC cell surfaces accurately, thus minimizing off-target effects on healthy tissues. Exosomes secreted by CRC cells naturally exhibit homing properties, further enhancing their targeting capabilities. A33-positive exosomes, for example, can specifically recognize CRC cell surface antigens, resulting in a significantly higher concentration of Adriamycin at tumor sites than in normal tissues, thereby improving tumor-targeting efficiency. When the A33 antibody and exosome complex (A33Ab-US-Exo/Dox) modified by magnetic nanoparticles was used, the uptake efficiency of tumor cells was improved, and the cardiac toxicity was significantly reduced [ 56 ] . Regarding multi-drug collaborative delivery, exosomes can simultaneously carry chemotherapy drugs, nucleic acid drugs, and protein drugs, thus enabling a multi-mechanism collaborative therapeutic approach. Studies have shown that exosomes loaded with oxaliplatin and miR-34a significantly inhibit CRC cell proliferation and migration by regulating the Wnt/β-catenin pathway [ 57 ] . Dual-drug co-loaded systems (e.g., Farnyl and paclitaxel) significantly reduce CRC cell activity by blocking the cell cycle and inhibiting microtubule depolymerization through synergistic mechanisms [ 58 ] . Another research team co-loaded doxorubicin and photosensitizer in HCT116 cell-derived exosomes and developed nanoprobes with chemotherapy, photodynamic therapy, and real-time monitoring functions, which showed more substantial tumor inhibition effects and lower systemic toxicity in vivo experiments [ 59 ] . Compared with synthetic nanoparticles, exosomes have low immunogenicity and long-term cycling properties, and their surface membrane proteins can reduce the risk of recognition by the immune system, thereby extending the cycle time in vivo. Studies have shown that hybrid exosomes formed by fusing mesenchymal stem cell-derived exosomes with folate-targeted liposomes show significantly extended tumor retention time in CT26 CRC models. In vivo experiments confirmed that the tumor growth inhibition rate of the hybrid exosomes treatment group was 2.8 times higher than that of traditional liposomes [ 60 ] . This finding aligns with nanoparticle engineering research, which indicates that CD47 modification can extend nanoparticle circulation time by up to sixfold. Exosomes naturally carry CD47 and other bioactive molecules, resulting in a longer circulation time than conventional PEG-liposomes [ 61 ] . Exosomes present an innovative strategy for precision drug delivery in CRC, offering natural targeting, high drug loading capacity, and low toxicity. They hold great potential for combination therapy and individualized medicine in the future. 2. Mediating tumor drug resistance The mechanism of exosome-mediated CRC resistance is a complex process involving multi-dimensional regulation. First, exosomes regulate drug efflux mechanisms and participate in the formation of drug resistance. By actively excreting cytotoxic drugs, exosomes significantly reduce intracellular drug concentration and form a protective barrier by wrapping chemotherapy drugs to weaken the killing effect of drugs. Secondly, resistant cells transmit resistance signals to sensitive cells through exosomes. For example, the exosomes of cetuximab-resistant CRC cells carry lncRNA-UCA1, which up-regulates the expression of myosin Ⅵ by binding miRNA-143, inducing sensitive cells to acquire proliferation ability and drug-resistant phenotype [ 62 ] . In addition, stromal cell-derived exosomes can induce drug resistance. For example, exosomes secreted by CAFs carry miRNA-92a-3p and miRNA-196b-5p, which induce sensitive cells to acquire stem-like phenotype and inhibit apoptosis, thereby enhancing chemotherapy resistance [ 63 ] . It is worth noting that CRC-resistant cell lines are associated with EMT, and molecules such as related proteins carried by stromal exosomes can induce EMT in CRC cells and reduce chemotherapy sensitivity [ 64 ] . In recent years, siRNA-mediated gene silencing techniques have shown significant potential in reversing chemotherapy resistance in CRC by targeting key resistance genes. For example, targeted silencing of VEGF by siRNA significantly inhibits CRC cell proliferation. Studies have shown that siRNA silencing SEMA4D gene combined with 5-FU on SW480 cells can increase the apoptosis rate and induce 5-FU resistance in CRC cells through caspase cascade reaction [ 65 ] . Exosomes are key agents driving CRC resistance through multiple mechanisms, and intervention strategies targeting the functional molecules carried by them may provide new directions for reversing chemotherapy resistance. 3. Immunotherapy Exosomes play a complex and bidirectional role in CRC immunotherapy, both promoting tumor immune evasion and serving as potential tools to enhance immune responses. On the one hand, exosomes inhibit anti-tumor immunity through a variety of mechanisms. They carry immune checkpoint molecules, such as PD-L1, that directly inhibit T cell activation and function and induce T cell depletion. At the same time, TGF-β and other immunosuppressive factors were transported to promote the expansion of Tregs and further inhibit the activity of effector T cells. In addition, exosomes impair T-cell initiation by delivering functional molecules that inhibit dendritic cell (DC) maturation and antigen presentation. On the other hand, exosomes also have potential as immunotherapeutic vectors. By genetically engineering or loading specific molecules, exosomes can be designed as tools to enhance anti-tumor immune responses. Exosomes loaded with tumor-associated antigens can be used as vaccines to stimulate the body to produce specific cytotoxic T lymphocyte responses, thereby improving the immune surveillance and clearance of CRC. In addition, exosomes can also carry co-stimulatory molecules or cytokines that enhance the antigen presentation capacities of DCs and T-cell activation. For example, Me49-DC-Exo has shown antitumor effects in CRC models by delivering an antigenic component of the parasite and stimulating a T-cell immune response [ 66 ] . Furthermore, exosomes can be used to provide immune checkpoint inhibitors, and experimental studies have shown that exosomes carrying PD-L1 siRNA and CTLA-4 siRNA can effectively inhibit tumor growth and enhance anti-tumor immune responses in tumor-bearing mouse models [ 67 ] . Therefore, an in-depth understanding of the mechanism of exosomes in the CRC immune microenvironment and rational use of their properties are expected to develop more effective CRC immunotherapy strategies. 4.4 Emerging frontiers In recent years, exosomes, as a crucial medium for intercellular communication, have demonstrated substantial potential in the fundamental mechanistic research of CRC, the advancement of liquid biopsy technologies, and the development of targeted therapies. Moving forward, research in this field is expected to focus on three primary trends: the synergy between multi-omics approaches and artificial intelligence (AI) to drive the clinical transformation of liquid biopsies, the precise targeting of exosome-mediated metastasis and immune escape mechanisms, and the integration of engineered exosomes with nanotechnology to facilitate innovations in drug delivery systems. The realization of these trends will not only depend on integrating interdisciplinary technologies but also require overcoming technical challenges related to standardized production and clinical translation, ultimately establishing a new paradigm for CRC precision medicine. (1) From biomarker discovery to clinical translation: multi-omics and AI collaboratively driving liquid biopsy 2.0. Exosomes, which carry nucleic acids, proteins, lipids, and other bioactive substances, have become a new "information treasure" in liquid biopsy. Compared with traditional circulating tumor DNA or circulating tumor cells, exosomal biomarkers have higher stability and tissue specificity. They can more sensitively reflect the molecular heterogeneity and dynamic evolution of CRC. However, it is difficult for single omics data to analyze the complex functions of exosomes comprehensively, so multi-omics integration and AI algorithm optimization will become the core strategy to improve diagnostic efficiency. The combined application of multiple omics (including genomics, transcriptomics, proteomics, and metabolomics) will reveal the synergistic mechanism of DNA mutations, non-coding RNAs, and transmembrane proteins in CRC exosomes. The application of AI technology in this area focuses on data dimensionality reduction and model optimization: deep learning algorithms can build multimodal predictive models by integrating exosomal miRNA profiles, metabolomics data, and clinicopathological features. Therefore, future liquid biopsy technologies based on exosomes will go beyond incremental advancements over traditional methods. By integrating multi-omics and AI, they are poised to bring a transformative shift in the field. This transformation will enable "Liquid Biopsy 2.0" for CRC screening and dynamic monitoring, enhancing early diagnosis and improving patient survival outcomes. This advanced method of liquid biopsy holds the potential to significantly enhance early CRC detection and ultimately improve patients' prognosis. (2) From mechanism analysis to precise intervention: targeting exosome-mediated metastasis and immune escape CRC metastasis and immune escape are the leading causes of treatment failure. Exosomes play an essential role in the communication between tumor cells and are involved in constructing the metastasis microenvironment and the induction of immunosuppression. An in-depth analysis of the mechanism of exosomes in CRC metastasis and immune escape will provide new ideas for developing targeted drugs or combination therapy. For example, inhibitors targeting exosome secretion, such as GW4869, could reduce exosome release, thereby inhibiting tumor metastasis and immune evasion. When combined with oxaliplatin, these inhibitors could enhance the sensitivity of CRC cells to chemotherapy [ 68 ] . In addition, blockers targeting exosomal target cell interactions can also be developed, for example, by blocking the exosome-mediated "don't eat me" signal through anti-CD47 antibodies, thereby inhibiting the binding of exosomes to target cells and reducing their biological effects. Furthermore, exosome inhibitors can be combined with immune checkpoint inhibitors, enhancing anti-tumor immune response and overcoming immune resistance. (3) From basic research to engineering applications: the fusion of engineered exosome vectors and biomimetic nanotechnology Natural exosomes are known for their excellent biocompatibility and inherent targeting capabilities; however, their drug-carrying capacity remains limited. By genetically engineering exosomes to express specific targeting ligands or to load therapeutic drugs, the targeting and efficacy of drugs can be improved. Moreover, the integration of engineered exosomes with biomimetic nanotechnology offers a promising avenue to overcome the limitations of current drug delivery systems, thus improving drug delivery efficiency and safety. For example, exosomes can be encapsulated in liposomes to form a new nano-drug delivery system. This system combines the targeting of natural membrane proteins with the high drug load of artificial carriers and can also improve the stability and bioavailability of drugs 60 . In addition, pH-sensitive exosomes release siRNA in the acidic TME or use heat-sensitive hydrogels to control the slow-release rate [ 69 ] . In the future, the fusion of engineered exosome carriers and biomimetic nanotechnology is expected to improve the targeting of drugs, which will provide new possibilities for the personalized precision treatment of CRC. 5 Innovation and limitation In this study, visualization tools such as CiteSpace, VOSviewer, RStudio, GraphPad, and SciExplorer were used to conduct an in-depth analysis of the research trends in the field of exosomes in CRC. CiteSpace has outstanding performance in co-citation analysis and knowledge graph construction, which can effectively outline the development track of this research domain. VOSviewer uses advanced web visualization technology to show research topics' relationships and knowledge structure clearly. RStudio, GraphPad, and SciExplorer provide robust support for data analysis and the generation of customized charts. By integrating these tools, this study can dig deep into the bibliometric data and reveal the research trends, hotspots, and future directions in this field. In addition to the traditional hotspot analysis, this study innovatively incorporates Burst Detection and Topic Modeling. The former is used to identify emerging research themes in a specific period, while the latter extracts potential themes and trends from massive literature to provide prospective guidance for future research. However, there are several limitations in this study. First, the inclusion of only the WOSCC database may lead to the omission of studies from other vital databases and non-English literature (e.g., Chinese core journals), thus affecting the comprehensiveness of the analysis results. Furthermore, the limitations inherent in citation analysis should be acknowledged. Although the number of citations can reflect a paper's influence, it does not fully represent its quality or innovation. Highly cited papers may also be subject to controversies or contain errors. Lastly, as the field of exosome research in CRC is rapidly evolving, with an increasing volume of literature, the analysis results may lag behind current developments and fail to capture the latest research progress fully. Therefore, future studies should consider incorporating a broader range of data sources and adopting updated analytical methodologies to obtain a more comprehensive understanding of the dynamic evolution of this field. 6 Conclusion The bibliometric analysis of exosomes in CRC reveals a notable growth trend in recent years, underscoring the academic community's growing attention to the role of exosomes in the pathogenesis, diagnosis, and treatment of CRC. China contributes to approximately half of the global research output in this field; however, despite strong domestic academic collaboration, international cooperation remains limited, which restricts the global impact of these studies. Currently, exosome research focuses on the role of non-coding RNAs, their application as biomarkers, the regulation of the TME, and the innovation of drug delivery systems. These studies not only provide new perspectives for early CRC diagnosis and personalized treatments but also offer valuable insights into future research directions. With the integration of multi-omics technologies and AI, the application of exosomes in liquid biopsy holds significant promise. Future research should prioritize strengthening international collaborations to facilitate the translation of basic research into clinical applications, ultimately achieving breakthroughs in CRC precision medicine. Table 1 Top 10 countries with the highest number of publications related to exosomes in CRC. Rank Country/region Article counts Centrality Percentage Total citations Average citation 1 CHINA 895 0.28 52.49% 33570 37.51 2 USA 221 0.4 12.96% 13017 58.90 3 ITALY 114 0.11 6.69% 6425 56.36 4 IRAN 94 0.08 5.51% 2422 25.77 5 GERMANY 71 0.18 4.16% 3778 53.21 6 JAPAN 70 0.03 4.11% 4658 66.54 7 SOUTH KOREA 61 0.07 3.58% 2611 42.80 8 AUSTRALIA 57 0.06 3.34% 4528 79.44 9 SPAIN 55 0.11 3.23% 2805 51.00 10 ENGLAND 51 0.2 2.99% 2443 47.90 Table 2 Top 10 productive institutions contributing to research on exosomes in CRC. Rank Institution Country Number of studies Total citations Average citation 1 Fudan University China 57 3639 63.84 2 Shanghai Jiao Tong University China 51 2492 48.86 3 Nanjing Medical University China 49 2779 56.71 4 Sun Yat-Sen University China 44 1728 39.27 5 Zhengzhou University China 42 2014 47.95 6 Central South University China 41 1261 30.76 7 Shandong University China 40 1559 38.98 8 Zhejiang University China 39 1266 32.46 9 China Medical University China 36 765 21.25 10 Southern Medical University China 30 1793 59.77 Table 3 Top 10 productive journals and co-cited journals related to exosomes in CRC. Rank Journal Article counts IF (2024) JCR (2024) Cited Journal Co-citations IF (2024) JCR (2024) 1 Cancers 68 4.5 Q1 Cancer Research 1076 12.5 Q1 2 International Journal of Molecular Sciences 63 4.9 Q1 PLOS ONE 1047 2.9 Q1 3 Frontiers in Oncology 61 3.5 Q2 Nature 965 50.5 Q1 4 Molecular Cancer 34 27.7 Q1 Oncotarget 959 - - 5 Oncotarget 30 - - Molecular Cancer 942 27.7 Q1 6 Cells 26 5.1 Q2 Cell 935 45.6 Q1 7 Frontiers in Cell and Developmental Biology 24 4.6 Q1 Scientific Reports 925 3.8 Q1 8 Journal of Extracellular Vesicles 23 15.5 Q1 Nature Communications 884 14.7 Q1 9 Scientific Reports 23 3.8 Q1 International Journal of Molecular Sciences 868 4.9 Q1 10 Cancer Cell International 20 5.3 Q1 Proceedings of the National Academy of Sciences of the United States of America 854 9.4 Q1 Table 4 Top 10 productive authors and co-cited authors related to exosomes in CRC. Rank Author Counts Co-cited author Citations 1 Simpson R.J. 16 Thery C. 358 2 Greening D.W. 14 Kalluri R. 331 3 Wang C. 14 Zhang Y. 286 4 Du L. 13 Li Y. 258 5 Li J. 12 Hoshino A. 242 6 Rai A. 11 Siegel R.L. 234 7 Coffey R.J. 10 Valadi H. 232 8 Ji H. 10 Li J. 232 9 Xu W. 10 Van N. 208 10 Zhang W. 10 Peinado H. 203 Table 5 Top 10 co-citation references related to exosomes in CRC Rank Title Journal author(s) Total citations 1 The biology, function, and biomedical applications of exosomes SCIENCE Kalluri R. 186 2 CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer MOLECULAR CANCER Hu J.L. 143 3 Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines JOURNAL OF EXTRACELLULAR VESICLES Welsh J.A. 134 4 Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19 THERANOSTICS Ren J. 129 5 Shedding light on the cell biology of extracellular vesicles NATURE REVIEWS MOLECULAR CELL BIOLOGY Van Niel G. 115 6 Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis NATURE COMMUNICATIONS Zeng Z.C. 104 7 Tumour exosome integrins determine organotropic metastasis NATURE Hoshino A. 92 8 Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells INTERNATIONAL JOURNAL OF CANCER Deng X. 83 9 Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p-TGF-β1 axis MOLECULAR CANCER Shang A.Q. 83 10 Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication NATURE CELL BIOLOGY Mathieu M. 83 Table 6 High-frequency keywords associated with exosomes in CRC. Rank Keyword Counts Rank Keyword Counts 1 colorectal-cancer 637 11 diagnosis 120 2 extracellular vesicles 509 12 hepatocellular-carcinoma 114 3 metastasis 279 13 epithelial-mesenchymal transition 109 4 biomarkers 193 14 chemoresistance 97 5 progression 153 15 serum 92 6 microRNAs 150 16 resistance 85 7 proliferation 146 17 stem-cells 83 8 invasion 134 18 prognosis 82 9 tumor microenvironment 131 19 prostate-cancer 80 10 liquid biopsy 129 20 angiogenesis 79 Abbreviations CRC Colorectal Cancer TME Tumor Microenvironment PMN Pre-metastatic Niche Formation WOSCC Web of Science Core Collection MCP Multinational Publications SCP Single-country Publications IF Impact Factor EMT Epithelial-mesenchymal Transition CAFs Cancer-associated Fibroblasts TAMS Tumor-associated Macrophages TRAIL Tumor Necrosis Factor-related Apoptosis-inducing Ligand MDSCs Myeloid-derived Suppressor Cells ITG Integrin LNM Lymph Node Metastasis DC Dendritic cell AI Artificial Intelligence Declarations Acknowledgements Thanks to the editors and reviewers for their hard work and important comments. Funding: This work was supported by the National Natural Science Foundation of China (No. 82204800), the National Outstanding Youth Science Fund Project of the National Natural Science Foundation of China (No. 8190150554), the Seventh Batch of National Traditional Chinese Medicine Experts' Academic Experience Inheritance Program, National Administration of Traditional Chinese Medicine (Document No.76,2022), the Graduate Research and Innovation Projects of Jiangsu Province (SJCX241010, SJCX240944), the Open Project of Zhenjiang Traditional Chinese Medicine Spleen and Stomach Disease Clinical Medicine Research Center (Zhenjiang Hospital Affiliated to Nanjing University of Chinese Medicine, Zhenjiang Hospital of Traditional Chinese Medicine) (No.SSPW2023-KF07), the Jiangsu Provincial Administration of Traditional Chinese Medicine Program (No. MS2023014), and the Jiangsu Provincial Medical Key Discipline (Laboratory) (No. ZDXYS202208). Author contributions: ML and YJ : Conceptualization, Investigation, Software, Visualization, Writing-original draft, Writing-review & editing. LS: Writing-original draft, Software, Writing-review & editing, Visualization. CX: Writing-review & editing, Software, Writing-original draft. JG: Writing-review & editing, Software, Writing-original draft. MY: Writing-review & editing, Software. WL: Writing-review & editing. QS: Writing-review & editing. JQ: Writing-review & editing.All authors read and approved the final manuscript. Competing interests: The authors declare no competing interests. Data availability: Research data are available from the corresponding author upon reasonable request. Ethics approval: Not applicable. Clinical trial number: Not applicable. Consent to publish declaration: Not applicable. Consent to participate declaration: Not applicable. Code availability: Not applicable. References Morgan E, Arnold M, Gini A, et al. 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The value of exosome-derived noncoding RNAs in colorectal cancer proliferation, metastasis, and clinical applications. Clin Transl Oncol . 2022;24(12):2305-2318. doi:10.1007/s12094-022-02908-6 Chang KH, Miller N, Kheirelseid EA, et al. MicroRNA-21 and PDCD4 expression in colorectal cancer. Eur J Surg Oncol . 2011;37(7):597-603. doi:10.1016/j.ejso.2011.04.001 Xu F, Xu L, Wang M, An G, Feng G. The accuracy of circulating microRNA-21 in the diagnosis of colorectal cancer: a systematic review and meta-analysis. Colorectal Dis . 2015;17(5):O100-7. doi:10.1111/codi.12917 Han L, Shi WJ, Xie YB, Zhang ZG. Diagnostic value of four serum exosome microRNAs panel for the detection of colorectal cancer. World J Gastrointest Oncol . 2021;13(8):970-979. doi:10.4251/wjgo.v13.i8.970 Zhang Y, Liu WS, Zhang XY, et al. Low expression of exosomal miR-150 predicts poor prognosis in colorectal cancer patients after surgical resections. Carcinogenesis . 2022;43(10):930-940. doi:10.1093/carcin/bgac059 Zou SL, Chen YL, Ge ZZ, Qu YY, Cao Y, Kang ZX. Downregulation of serum exosomal miR-150-5p is associated with poor prognosis in patients with colorectal cancer. Cancer Biomark . 2019;26(1):69-77. doi:10.3233/cbm-190156 Cho WC, Kim M, Park JW, Jeong SY, Ku JL. Exosomal miR-193a and let-7g accelerate cancer progression on primary colorectal cancer and paired peritoneal metastatic cancer. Transl Oncol .2021;14(2):101000. doi:10.1016/j.tranon.2020.101000 Gherman A, Balacescu L, Popa C, et al. Baseline Expression of Exosomal miR-92a-3p and miR-221-3p Could Predict the Response to First-Line Chemotherapy and Survival in Metastatic Colorectal Cancer. Int J Mol Sci . 2023;24(13)doi:10.3390/ijms241310622 Sun B, Li Y, Zhou Y, et al. Circulating exosomal CPNE3 as a diagnostic and prognostic biomarker for colorectal cancer. J Cell Physiol . 2019;234(2):1416-1425. doi:10.1002/jcp.26936 Wang X, Chen L, Zhang W, Sun W, Huang J. Colorectal Cancer-Derived Exosomes Impair CD4(+) T Cell Function and Accelerate Cancer Progression via Macrophage Activation. Cancer Biother Radiopharm .2025;40(3):185-195. doi:10.1089/cbr.2024.0032 Zhi J, Li Y, Jia Y. Research advances of exosome-derived lncRNA in the development of colorectal cancer. CHINESE JOURNAL OF CLINICAL ONCOLOGY; 2021, 48(20): 1066-1070. DOI: 10.12354/j.issn.1000-8179.2021.20201224 Wang BY, Wei YB, Yang Y, et al. Research progress of exosome-related factors in the diagnosis and treatment of colorectal cancer. CHINESE JOURNAL OF CLINICAL ONCOLOGY. 2023; 50: 643-648. DOI: 10.12354/j.issn.1000-8179.2023.20230193 Wang Q, Jiang ZY, Zhang Y, et al. Expression and clinical significance of lncRNA PCGEM1 and miR-152-3p in colorectal cancer tissues and serum exosomes. Journal of Guangxi Medical University. 2023;40: 1863-1870. DOI: 10.16190/j.cnki.45-1211/r.2023.11.014 Pan B, Qin J, Liu X, et al. Identification of Serum Exosomal hsa-circ-0004771 as a Novel Diagnostic Biomarker of Colorectal Cancer. Front Genet . 2019;10:1096. doi:10.3389/fgene.2019.01096 Zhou H, He X, He Y, Ou C, Cao P. Exosomal circRNAs: Emerging Players in Tumor Metastasis. Front Cell Dev Biol . 2021;9:786224. doi:10.3389/fcell.2021.786224 Yu Q, Zhang Y, Tian Y, et al. Exosomal Circ_FMN2 Derived from the Serum of Colorectal Cancer Patients Promotes Cancer Progression by miR-338-3p/MSI1 Axis. Appl Biochem Biotechnol . 2023;195(12):7322-7337. doi:10.1007/s12010-023-04456-3 Qiao XX, Shi HB, Xiao L. Serum exosomal hsa-circ-0004771 modulates the resistance of colorectal cancer to 5-fluorouracil via regulating miR-653/ZEB2 signaling pathway. Cancer Cell Int . 2023;23(1):243. doi:10.1186/s12935-023-03072-9 Tang A, Shu Q, Jia S, Lai Z, Tian J. Adipose Mesenchymal Stem Cell-Derived Exosomes as Nanocarriers for Treating Musculoskeletal Disorders. Int J Nanomedicine . 2024;19:13547-13562. doi:10.2147/ijn.S486622 Sharifi-Azad M, Fathi M, Cho WC, et al. Recent advances in targeted drug delivery systems for resistant colorectal cancer. Cancer Cell Int . 2022;22(1):196. doi:10.1186/s12935-022-02605-y Wang ZH, Chu M, Yin N, et al. Biological chemotaxis-guided self-thermophoretic nanoplatform augments colorectal cancer therapy through autonomous mucus penetration. Sci Adv . 2022;8(26):eabn3917. doi:10.1126/sciadv.abn3917 de Dios-Pérez I, González-Garcinuño Á, Muñoz-Barroso I, Martín Del Valle EM. A Synergistic Approach Therapy for Colorectal Cancer Based on Exosomes and Exploitation of Metabolic Pathways. J Pharm Sci . 2024;113(4):1038-1046. doi:10.1016/j.xphs.2023.10.017 Qian R, Jing B, Jiang D, et al. Multi-antitumor therapy and synchronous imaging monitoring based on exosome. Eur J Nucl Med Mol Imaging . 2022;49(8):2668-2681. doi:10.1007/s00259-022-05696-x Wang X, Li D, Li G, et al. Enhanced Therapeutic Potential of Hybrid Exosomes Loaded with Paclitaxel for Cancer Therapy. Int J Mol Sci . 2024;25(7)doi:10.3390/ijms25073645 Chen H, Wang L, Zeng X, et al. Exosomes, a New Star for Targeted Delivery. Front Cell Dev Biol . 2021;9:751079. doi:10.3389/fcell.2021.751079 Ahmadi M, Jafari R, Mahmoodi M, Rezaie J. The tumorigenic and therapeutic functions of exosomes in colorectal cancer: Opportunity and challenges. Cell Biochem Funct .2021;39(4):468-477. doi:10.1002/cbf.3622 Shakerian N, Darzi-Eslam E, Afsharnoori F, et al. Therapeutic and diagnostic applications of exosomes in colorectal cancer. Med Oncol .2024;41(8):203. doi:10.1007/s12032-024-02440-3 Lee TY, Liu CL, Chang YC, et al. Increased chemoresistance via Snail-Raf kinase inhibitor protein signaling in colorectal cancer in response to a nicotine derivative. Oncotarget . 2016;7(17):23512-20. doi:10.18632/oncotarget.8049 Rashidi G, Rezaeepoor M, Mohammadi C, Solgi G, Najafi R. Inhibition of semaphorin 4D enhances chemosensitivity by increasing 5-fluorouracile-induced apoptosis in colorectal cancer cells. Mol Biol Rep . 2020;47(9):7017-7027. doi:10.1007/s11033-020-05761-4 Zhu S, Lu J, Lin Z, et al. Anti-Tumoral Effect and Action Mechanism of Exosomes Derived From Toxoplasma gondii-Infected Dendritic Cells in Mice Colorectal Cancer. Front Oncol . 2022;12:870528. doi:10.3389/fonc.2022.870528 Li J, Chen Y, Liao M, et al. Exosomes-delivered PD-L1 siRNA and CTLA-4 siRNA protect against growth and tumor immune escape in colorectal cancer. Genomics .2023;115(4):110646. doi:10.1016/j.ygeno.2023.110646 Sinha D, Roy S, Saha P, Chatterjee N, Bishayee A. Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy. Cancers (Basel) .2021;13(2)doi:10.3390/cancers13020326 Al-Ani SA, Lee QY, Maheswaran D, et al. Potential of Exosomes as Multifunctional Nanocarriers for Targeted Drug Delivery. Mol Biotechnol .2024;doi:10.1007/s12033-024-01268-6 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6450425","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":465416924,"identity":"9cbc487b-6cef-43fc-a0b4-221586de56cb","order_by":0,"name":"Man Lu","email":"","orcid":"","institution":"No. 1 Clinical Medical College, Nanjing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Man","middleName":"","lastName":"Lu","suffix":""},{"id":465416925,"identity":"aac6a8a8-6234-419f-b063-6e83b0241520","order_by":1,"name":"Yanjie Jiang","email":"","orcid":"","institution":"Affiliated Hospital of Nanjing 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16:53:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":549882,"visible":true,"origin":"","legend":"\u003cp\u003eAnnual publication totals and trends.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/c63236266c4b93f4bcf1e523.png"},{"id":83853735,"identity":"a8d173b4-45f8-4dd1-81e3-0026abefb537","added_by":"auto","created_at":"2025-06-03 16:53:59","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":813071,"visible":true,"origin":"","legend":"\u003cp\u003eVisual mapping of countries/regions analysis.\u003c/p\u003e\n\u003cp\u003e(A) Distribution of research output by countries/regions\u003c/p\u003e\n\u003cp\u003e(B) Line graph depicting the number of publications by countries/regions.\u003c/p\u003e\n\u003cp\u003e(C) Network of international research collaborations.\u003c/p\u003e\n\u003cp\u003e(D) Distribution of corresponding authors' countries.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/115c44bc66d180523cea14a4.png"},{"id":83854043,"identity":"5b8b64be-f4e0-4e74-9f68-709d254e1558","added_by":"auto","created_at":"2025-06-03 17:01:59","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1105022,"visible":true,"origin":"","legend":"\u003cp\u003eNetworks of institutional collaboration.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/6c1edc1ee18588f57914b352.png"},{"id":83853737,"identity":"f6b2eef9-e374-475b-b6e9-cb675f0d697a","added_by":"auto","created_at":"2025-06-03 16:53:59","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1758794,"visible":true,"origin":"","legend":"\u003cp\u003eVisual mapping of journal and co-cited journal analysis.\u003cbr\u003e\n(A) Density map of journals and co-cited journals.\u003cbr\u003e\n(B) Co-citation network of journals.\u003cbr\u003e\n(C) Dual-map overlay of journals.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/4c58879cd0de4b136cc95913.png"},{"id":83854643,"identity":"f980972f-c6a0-4fe1-85de-693a1aa3081d","added_by":"auto","created_at":"2025-06-03 17:09:59","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1603572,"visible":true,"origin":"","legend":"\u003cp\u003eVisual mapping of author and co-cited author analysis.\u003cbr\u003e\n(A) Cooperation network of authors.\u003c/p\u003e\n\u003cp\u003e(B) Co-citation network of authors.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/f889fd2276dfef0ed9bc6cc3.png"},{"id":83853734,"identity":"696a817a-8721-4d8c-8dcb-89ee4860072a","added_by":"auto","created_at":"2025-06-03 16:53:59","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":2190663,"visible":true,"origin":"","legend":"\u003cp\u003eVisual mapping of co-cited literatureanalysis.\u003c/p\u003e\n\u003cp\u003e(A) Co-cited network of literature.\u003c/p\u003e\n\u003cp\u003e(B) Clustering of topics formed by co-cited literature.\u003c/p\u003e\n\u003cp\u003e(C) Peak map of co-cited literature clustering over time.\u003c/p\u003e\n\u003cp\u003e(D) Bursting map of cited literature.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/d709bbd111012506561f712c.png"},{"id":83854042,"identity":"da6d5da5-6651-482b-92fe-d5faefc85f7f","added_by":"auto","created_at":"2025-06-03 17:01:59","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":2777222,"visible":true,"origin":"","legend":"\u003cp\u003eVisual mapping of high-frequency keywords analysis.\u003c/p\u003e\n\u003cp\u003e(A) Network of high-frequency keywords.\u003c/p\u003e\n\u003cp\u003e(B) Density map of high-frequency keywords.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/0ea8946bf5f59cceea1fad92.png"},{"id":83853741,"identity":"be1d59e5-ca11-41d6-9672-661292f69a47","added_by":"auto","created_at":"2025-06-03 16:53:59","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":400637,"visible":true,"origin":"","legend":"\u003cp\u003eVisual mapping of trend topics analysis.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/122a01a0d7afdebc180a039d.png"},{"id":88964985,"identity":"feffa3f6-4706-40c1-b35c-783031a867db","added_by":"auto","created_at":"2025-08-13 08:48:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":15703513,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6450425/v1/ec1eb0e4-74ef-4480-a59c-1782a12aee36.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Global trends and future perspectives on exosomes in colorectal cancer: a comprehensive bibliometric analysis (2003-2024)","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eCRC is the third most common malignant tumor in the world and the second largest cause of cancer-related death, with more than 1.9\u0026nbsp;million new cases and approximately 930,000 deaths every year\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Although the popularization of screening techniques (such as colonoscopy and fecal DNA testing) and the use of targeted therapies (anti-EGFR /VEGF therapy) have significantly improved clinical management\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, the prognosis of CRC is still not optimistic, and recurrence and metastasis are still the leading causes of treatment failure. Therefore, it is crucial to deeply understand CRC pathogenesis and development and search for new diagnostic biomarkers and therapeutic targets.\u003c/p\u003e \u003cp\u003eIn recent years, exosomes have received extensive attention as an essential medium of intercellular communication. Such nanoscale vesicles with a 30-150nm diameter are released by the fusion of intracellular polyvesicles with cell membranes. They carry abundant bioactive molecules, including nucleic acids, proteins, and lipids, which can participate in tumors' occurrence, development, metastasis, and drug resistance by regulating gene expressions, signaling pathways, and immune response of target cells\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. There is increasing evidence that exosomes play an important and complex role in the occurrence and progression of CRC. On the one hand, exosomes released by tumor cells can promote the proliferation, invasion, and metastasis of tumor cells and inhibit the function of immune cells, thus promoting the development of tumors. On the other hand, some exosomes may play a role in tumor suppression, for example, by delivering tumor suppressor genes or activating immune responses\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. In addition, exosomes are also considered potential diagnostic markers for early diagnosis and prognosis assessment of CRC.\u003c/p\u003e \u003cp\u003eAlthough the exploration of exosomes in CRC research continues to deepen, the existing review literature usually lacks systematic analysis of research trends, international cooperation models, and the evolution of hotspots, and the current bibliometric analysis of CRC exosomes is still blank. Based on the WOSCC database and combined with tools such as CiteSpace, VOSviewer, and RStudio, this study conducted a multi-dimensional comprehensive analysis of the literature in this field over the past 20 years. The purpose of this study is to (1) reveal the knowledge structure and evolution of this field; (2) identify collaboration networks of key authors, institutions, and countries; (3) predict future research directions and discuss current challenges and opportunities. The study results will provide a data-driven decision-making basis for scholars in related fields and promote the application of exosomes in the clinical transformation of CRC.\u003c/p\u003e"},{"header":"2 Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data source\u003c/h2\u003e \u003cp\u003eThe data for this study was sourced from the WOSCC database, a widely recognized and comprehensive multidisciplinary journal citation database known for its extensive literature coverage and high-quality citation indexes. Each record in the WOSCC database includes metadata such as publication year, author information, institutional affiliation, document type, research field, journal title, citation counts, and reference lists. This rich data set provides researchers with valuable resources, enabling in-depth analysis of citation patterns and research trends in academic literature. Therefore, the WOSCC database is considered an ideal choice for bibliometric analysis, helping to track the development of scholarly research and reveal knowledge flow and educational influence across different disciplines.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Search strategy\u003c/h2\u003e \u003cp\u003eWe systematically searched and compiled relevant publications on exosomes in CRC from January 1, 2003, to December 21, 2024. The inclusion criteria were as follows: (1) full-text publications related to exosomes in CRC, (2) articles and reviews written in English. The exclusion criteria included: (1) publications unrelated to exosomes in CRC; (2) certain document types, including proceedings papers, meeting abstracts, editorial materials, early access articles, letters, retracted publications, book chapters, and corrections. The search was performed on a single day to ensure consistency in data collection. Data were exported in the format of \u0026ldquo;full records and cited references\u0026rdquo; as plain text, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, which outlines the screening process. The search formula used was as follows: (((((((((((((((((TS=(\"Colorectal Neoplasms\")) OR TS=(\"Colorectal Neoplasm\")) OR TS=(\"Neoplasm, Colorectal\")) OR TS=(\"Neoplasms, Colorectal\")) OR TS=(\"Colorectal Tumors\")) OR TS=(\"Colorectal Tumor\")) OR TS=(\"Tumor, Colorectal\")) OR TS=(\"Tumors, Colorectal\")) OR TS=(\"Colorectal Cancer\")) OR TS=(\"Cancer, Colorectal\")) OR TS=(\"Cancers, Colorectal\")) OR TS=(\"Colorectal Cancers\")) OR TS=(\"Colorectal Carcinoma\")) OR TS=(\"Carcinoma, Colorectal\")) OR TS=(\"Carcinomas, Colorectal\")) OR TS=(\"Colorectal Carcinomas\")) OR TS=(CRC) AND (((((TS=(exosomes)) OR TS=(exosome)) OR TS=(\"extracellular vesicle\")) OR TS=(\"extracellular vesicles\")) OR TS=(exosomal)) OR TS=(\"extracellular vesicle\"). A bibliometric analysis was conducted on the collected publications for data evaluation and visualization. Two researchers independently analyzed and cross-verified the data to ensure accuracy and reliability.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data analysis\u003c/h2\u003e \u003cp\u003eThis study employed many data analysis approaches, integrating quantitative and qualitative techniques to examine research trends, collaborations, and knowledge structures. Quantitative analysis focused on annual publication counts, rankings of top contributors (countries, institutions, authors, and journals), and temporal trends in research output. Qualitative analysis explored intellectual networks through co-citation and collaboration network analysis, identifying relationships among authors, journals, and references. Advanced bibliometric tools were utilized: CiteSpace (version 6.2.R4) for co-citation, co-word, and keyword analysis to visualize research hotspots and frontiers; VOSviewer (version 1.6.18) for constructing and clustering bibliometric networks; RStudio (bibliometrix package) for thematic evolution and research structure analysis; and GraphPad (version 8.0.2) and SciExplorer for data visualization and statistical analysis. This multi-tool approach ensured a comprehensive examination of the research landscape, providing insights into publication trends, collaborative networks, and emerging research directions over the past two decades.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Global trend of publications\u003c/h2\u003e \u003cp\u003eA total of 1,705 publications related to exosomes in CRC were retrieved from the WOSCC database, comprising 1,103 original research articles (65%) and 602 review articles (35%). These publications originated from 76 countries/regions, involving 2,240 institutions and 9,113 authors. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the annual publication volume and its developmental trajectory. The x-axis represents the years, while the left and right y-axes indicate the annual publication count and cumulative publication volume, respectively. The light blue bars denote the annual publication count, and the blue curve represents the cumulative publication volume. The data reveal a significant increase in yearly publications since 2003, which can be categorized into three distinct phases. In the initial phase (2003\u0026ndash;2013), the annual publication count remained below 10, indicating that exosome research in CRC was nascent and had not yet garnered widespread attention. The second phase (2014\u0026ndash;2020) witnessed a substantial increase in publications, marking a period of rapid development. During this phase, researchers began to recognize the potential of this field, leading to a surge in academic interest and a proliferation of research outputs. In the third phase (post-2020), the field has continued to attract significant attention, with an annual publication volume exceeding 260 articles. Exosome research has become a prominent focus in CRC, consistently attracting experts and scholars for in-depth exploration and driving innovative outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Analysis of countries/regions\u003c/h2\u003e \u003cp\u003eAs of December 2024, a total of 76 countries and regions worldwide have conducted research on exosomes in CRC (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Among the top ten countries/regions by publication volume (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), China contributes over 50% of the global output, and its cumulative citation count has reached 33,570, far surpassing other countries/regions. However, China ranks lower in terms of the average citations per paper (37.51), indicating that the overall quality of its research is relatively lower. The United States ranks second with 221 publications and 13,017 cumulative citations, while its centrality score of 0.4 places it at the top among all countries/regions.\u003c/p\u003e \u003cp\u003eWe further analyzed the collaboration networks among countries (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC) and the countries of corresponding authors (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). In this context, \"multinational publications(MCP)\" refer to papers co-authored by researchers from different countries, while \"single-country publications(SCP)\" are those authored by researchers from the same country. The results show that China and the United States have a relatively close collaboration, whereas academic cooperation within most countries primarily occurs domestically, with limited international academic exchange and collaboration. Notably, MCPs constitute less than one-fifth of the total publications.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Analysis of institutions\u003c/h2\u003e \u003cp\u003eA total of 2,240 institutions have systematically published research on exosomes in CRC. The top ten institutions by publication volume are all located in China (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Fudan University leads in publication count (57), total citations (3,639), and average citations per paper (63.84). The collaboration network among institutions is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, where arcs of different colors represent collaborative relationships, with thicker lines indicating stronger collaborations. Shanghai Jiao Tong University and Fudan University exhibit the most extensive and robust collaborations, primarily with institutions such as Tongji University, Shanghai University of Traditional Chinese Medicine, Zhejiang University, and Nanjing Medical University, which are predominantly located in coastal regions. Therefore, we advocate for enhanced inter-regional institutional collaborations to break down academic barriers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Analysis of journals and co-cited journals\u003c/h2\u003e \u003cp\u003eThis study comprehensively analyzed the top ten productive journals and co-cited journals based on publication volume, citation counts, impact factor (IF), and journal quartiles. According to publication volume (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), Cancers leads with 68 publications, followed by the International Journal of Molecular Sciences (63) and Frontiers in Oncology (61). This aligns with the journal publication density map in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA. Among these high-output journals, Molecular Cancer boasts the highest IF of 27.7, highlighting its leading position in oncology and related fields.\u003c/p\u003e \u003cp\u003eThe academic influence of journals is often assessed by their co-citation frequency. Journals with high co-citation counts typically wield significant impact in the academic community, playing a crucial role in advancing scientific research. Based on Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB and Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the most co-cited journals are Cancer Research (1,076), PLOS ONE (1,047), and Nature (965). Notably, Nature ranks high in co-citation counts and has the highest IF among the top ten co-cited journals at 50.5. Furthermore, 90% of these co-cited journals are in the Q1 quartile, underscoring their high impact and authority in the academic field.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC illustrates the distribution of journals and the relationships between citing and cited journals through a dual overlay map, highlighting the thematic distribution of academic publications in this field. The left and right sides represent citing and cited journals, respectively, with colored lines indicating citation links, where thicker lines denote stronger connections. Two primary citation pathways are identified: research published in journals within the molecular/biology/genetics domain is predominantly cited by journals in the molecular/biology/immunology and medicine/medical/clinical domains.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Analysis of authors and co-cited authors\u003c/h2\u003e \u003cp\u003eIn this study, 9,113 authors contributed to publishing all research outcomes. Among them, 146 authors had more than 50 co-citations, indicating their significant academic influence. Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e lists the top ten authors by publication volume, who collectively contributed 120 papers, accounting for 7% of the related papers in the field. Specifically, Simpson R.J. ranks first with 16 published papers, followed by Greening D.W. (14), Wang C. (14), Du L. (13), and Li J. (12). To provide a more precise representation of the collaborative network and academic influence among these scholars, we utilized CiteSpace software for a visual analysis of the author network, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA.\u003c/p\u003e \u003cp\u003eWhen the works of two or more authors are cited together within the same reference list of one or more papers, these authors are said to have a co-citation relationship or are called co-cited authors. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the top ten co-cited authors have been cited over 2,500 times collectively. Figure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB presents the co-citation network visualization, where each node represents an author, and the node size corresponds to the citation frequency. In the co-citation network, Thery C. has the highest citation count (358), followed by Kalluri R. (331) and Zhang Y. (286). The widespread citation of these authors\u0026rsquo; works reflects their profound impact and academic standing in the field.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Analysis of co-cited references and reference burst\u003c/h2\u003e \u003cp\u003eWe conducted a visual analysis of co-cited references from 2003 to 2024 using CiteSpace, resulting in a network consisting of 1,127 nodes and 5,638 links (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eA). Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e lists the top ten most co-cited references related to exosomes in CRC. The three most frequently cited papers are: Kalluri R. et al., 2021, Science\u003csup\u003e3\u003c/sup\u003e; Hu J.L. et al., 2019, Molecular Cancer\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e; and Welsh J.A. et al., 2024, Journal of Extracellular Vesicles\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Notably, Kalluri R. and colleagues\u0026rsquo; seminal review, \"The biology, function, and biomedical applications of exosomes,\" published in Science, has been pivotal in advancing exosome research. This comprehensive review outlines the fundamental concepts, biological characteristics, and potential clinical applications of exosomes, laying a solid foundation for subsequent research. Among these influential papers, three focus primarily on the fundamental biological functions of exosomes, including their roles in cellular communication, secretory pathways, and cellular uptake, representing key foundational work in the exosome field. Six papers emphasize the specific roles of exosomes in CRC, particularly their involvement in tumor progression, metastasis, chemotherapy resistance, and modulation of the TME. One paper addresses the need for standardization in exosome research, promoting methodological advancements in the field.\u003c/p\u003e \u003cp\u003eCluster analysis of co-cited references (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eB) and the temporal evolution of co-citation clusters (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eC) reveal distinct research trends. Early hotspots included tumor-associated antigens (cluster 7), promoter assays (cluster 11), and CCA (cluster 15). Mid-term hotspots encompassed the secretome (cluster 5), CRMP-2 (cluster 9), blood-brain barrier (cluster 10), sunitinib (cluster 13), and circRHOBTB3 (cluster 16). Current popular research directions focus on CRC (cluster 0), microsatellite instability (cluster 1), fibroblasts (cluster 3), circRNA (cluster 5), liquid biopsy (cluster 6), hypoxia (cluster 8), targeted therapy (cluster 12), and circulating tumor cells (cluster 14).\u003c/p\u003e \u003cp\u003eAdditionally, we identified the top 50 references with the most strongest citation bursts in the field, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eD. Early references typically exhibited higher citation intensity, likely due to their pioneering nature, primarily focusing on exosome discovery and fundamental functions. While later references continued to garner significant citations, there was a slight decline in intensity compared to earlier works, likely reflecting the broadening of the field and the emergence of new research areas. These later studies primarily focus on the clinical applications of exosomes in CRC diagnosis, prognosis, and treatment. The paper with the highest citation burst intensity is by Hoshino A.\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, published in Nature in 2015, with an intensity of 35.13. Known for its groundbreaking nature, this study explores the critical roles of exosomes in tumor metastasis, immune evasion, and drug resistance, leading to widespread citations in subsequent research. Following closely are works by Ogata-Kawata H. (PLOS ONE, 2014) with an intensity of 33.42, and Matsumura T. (British Journal of Cancer, 2015) with an intensity of 30.12. These studies are considered seminal and have significantly influenced subsequent research. Notably, as of 2024, six studies closely related to this field continue to experience citation bursts, with the most notable being the work by Sung H. et al., published in 2021, which has maintained a high citation rate since its publication.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.7 Analysis of keywords and keywords burst\u003c/h2\u003e \u003cp\u003eIn the study of the application of exosomes in CRC, keyword clustering analysis has been used to identify different research themes and development trends. According to the co-occurrence analysis of keywords in VOSviewer, in addition to \"colorectal cancer\" (637) and \"extracellular vesicles\" (509), other popular keywords include \"metastasis\" (279), \"biomarkers\" (193), and \"progression\" (153) (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eA and \u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eB). By removing irrelevant keywords and constructing a network containing 165 keywords that appear at least 15 times, five distinct research clusters were identified.\u003c/p\u003e \u003cp\u003eThe first cluster of keywords (purple) primarily focuses on the detection of biomarkers in exosomes using liquid biopsy technology for the diagnosis, prognostic evaluation, and recurrence monitoring of CRC. Core keywords include \"liquid biopsy,\" \"biomarkers,\" \"diagnostic biomarkers,\" \"prognostic biomarker,\" \"prognostic value,\" \"cell-free DNA,\" \"microRNAs,\" etc. The emphasis is on the clinical application of liquid biopsy and the clinical significance of these biomarkers. The second cluster of keywords (yellow) involves tumor cells' proliferation, invasion, and metastasis and the regulatory role of non-coding RNAs (such as circRNA and lncRNA) in these processes. Keywords such as \"epithelial-mesenchymal transition (EMT),\" \"long noncoding RNA,\" \"circRNA,\" \"cell proliferation,\" \"tumorigenesis,\" \"invasion,\" \"migration,\" \"hepatocellular carcinoma,\" etc., indicate that the research mainly focuses on the biological behaviors of tumor cells and their molecular mechanisms, with a particular emphasis on the role of non-coding RNAs in tumor initiation and progression. The third cluster of keywords (blue) centers around exosome biosynthesis, secretion, composition, and intercellular communication roles. Keywords like \"exosome,\" \"biogenesis,\" \"intercellular communication,\" \"proteomics,\" \"vesicles,\" \"mass spectrometry,\" etc., focus on the biological characteristics of exosomes and their role in intercellular communication. The fourth cluster of keywords (green) explores the role of exosomes in remodeling the TME and in multidrug resistance. Keywords such as \"extracellular vesicles,\" \"cancer stem cells,\" \"cancer-associated fibroblasts (CAFs),\" \"tumor microenvironment,\" \"drug resistance,\" \"immunotherapy,\" \"delivery,\" and \"nanoparticles\" mainly discuss the complexity of the TME and its impact on treatment responses, particularly in terms of drug resistance and potential immunotherapy targets. The fifth cluster of keywords (red) focuses on the progression, metastasis mechanisms, and potential therapeutic targets in CRC. Keywords such as \"colorectal cancer,\" \"metastasis,\" \"expression,\" \"progression,\" \"inflammation,\" \"angiogenesis,\" and \"macrophages\" indicate that the research aims to reveal the biological mechanisms of CRC and explore new therapeutic targets to improve patient prognosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.8 Research trends evolution\u003c/h2\u003e \u003cp\u003eWe performed a visual analysis of the key trends and topics related to exosomes in CRC over the past fifteen years using RStudio (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e). The study revealed a rising frequency of keywords such as \"tumor-associated macrophages (TAMs),\" \"polarization,\" \"promotes metastasis,\" and \"progression,\" indicating that exosome-mediated remodeling of the TME has gradually become a research focus in this field, particularly in its roles in promoting tumor metastasis and immune evasion. Additionally, the increasing frequency of keywords like \"biomarkers,\" \"diagnostic biomarkers,\" \"circulating microRNAs,\" \"serum,\" and \"plasma\" reflects growing attention to the identification of clinically relevant biomarkers from exosomes. Notably, exosomes have demonstrated substantial potential not only in tumor biomarker discovery and microenvironment regulation but also as therapeutic tools, particularly in drug delivery. Although the keywords directly related to therapy remain relatively limited in current research, the potential of engineered exosomes as drug carriers is becoming more apparent. Overall, the research focus is progressively shifting from basic biological mechanisms to clinical applications and technological innovations, playing a significant role in early diagnosis, treatment monitoring, and personalized therapy.\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.1 General information\u003c/h2\u003e \u003cp\u003eOver the past two decades, there has been a significant increase in publications on exosomes in CRC, highlighting the potential of this field in oncology research. Through bibliometric analysis, this paper reveals the evolution of research in this field: from the initial exploratory phase (2003\u0026ndash;2013) to the period of rapid innovation (2014\u0026ndash;2020) and finally to the surge in scientific research (after 2020). This development trajectory reflects the growing recognition within the academic community of the central role of exosomes in CRC initiation and progression, as well as their dual value as diagnostic and prognostic biomarkers and therapeutic targets. China has made the most considerable contribution in this area, accounting for over 50% of global research output. However, the relatively low average citation count per article suggests that the quality and impact of research in the country still have room for improvement. Collaboration network analysis indicates that while domestic academic collaborations in China are relatively strong, international collaborations remain limited. This highlights the importance of strengthening international and cross-institutional collaborations to enhance the global impact of exosome research further. Notably, high-impact papers are predominantly published in Q1 journals, and foundational works by scholars such as Thery C. and Kalluri R. occupy central positions in the citation network, indicating the field's reliance on the interdisciplinary integration of molecular biology and clinical oncology. Overall, these trends suggest that the role of exosomes in CRC research is steadily maturing, driving the exploration of new diagnostic and therapeutic approaches in the field.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Citation bursts\u003c/h2\u003e \u003cp\u003eCitation explosion refers to the phenomenon where literature is frequently cited over a short period, reflecting the emergence of research hotspots and shifts in scholarly focus. Analyzing highly cited literature allows for effectively tracking emerging issues and development trends related to exosomes in CRC. Early research (2012\u0026ndash;2017) primarily focused on the fundamental biological functions of exosomes and their roles in cancer progression, thereby laying the foundation for exosome research. Mid-term research (2017\u0026ndash;2020) increasingly focused on the clinical applications of exosomes, particularly their potential as diagnostic biomarkers and therapeutic targets, thus facilitating the clinical translation of related technologies. Recent studies (2020\u0026ndash;2024) have further explored the molecular mechanisms of exosomes in CRC and their clinical applications. Notably, six papers closely related to the theme are currently experiencing citation bursts. A detailed analysis of these papers reveals the current hot topics in exosomes in CRC: (1) Exosomal non-coding RNAs and CRC progression: three of the six papers undergoing bursts are related to this topic. Shang AQ et al.\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e indicated that exosomal circPACRGL promotes CRC via the miR-142-3p/miR-506-3p-TGF-β1 axis; Wang XY et al.\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e demonstrated that exosome-delivered circRNAs promote glycolysis through the miR-122-PKM2 axis, which in turn induces CRC drug resistance; Zhao SL et al.\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e found that tumor-derived exosome miR-934 induced macrophage M2 polarization and promoted CRC liver metastasis. Consequently, regulating CRC progression by exosomal non-coding RNAs has become a significant focus of current research. Non-coding RNAs, such as circRNAs and miRNAs, regulate tumor cell proliferation, metastasis, and drug resistance through interactions with intracellular molecules. Investigating the mechanisms underlying the action of these molecules can deepen our understanding of CRC pathogenesis and provide theoretical support for the development of novel diagnostic biomarkers and therapeutic targets. (2) Application of exosomes as biomarkers: the potential of exosomes as biomarkers has been emphasized in studies by Kalluri R et al. \u003csup\u003e3\u003c/sup\u003eand Hoshino A et al.\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Kalluri R et al. comprehensively elaborated on the biological properties and functions of exosomes, establishing a foundation for further research on their role in CRC. They also pointed out that proteins and nucleic acids carried by exosomes can reflect tumor characteristics and serve as potential biomarkers. Hoshino A et al. expanded the application of exosomes as biomarkers across various cancers, offering a systematic approach to discovering CRC-specific biomarkers. Both studies emphasize the importance of exosomes as a liquid biopsy, foreseeing their promising applications in CRC diagnosis, prognostic assessment, and therapeutic monitoring, which may provide a basis for personalized treatment. (3) Exosomes regulate the TME: Zhao SL et al.\u003csup\u003e11\u003c/sup\u003e found that exosomes secreted by CRC cells are enriched in miR-934, which targets and inhibits pro-inflammatory factor expression, induces macrophage polarization to the M2 type, and upregulates M2 markers (e.g., CD206 and Arg1). Animal experiments demonstrated that the injection of miR-934-containing exosomes significantly increased the incidence of liver metastasis. This study demonstrated that exosomes play a crucial role in regulating the TME, offering new insights into the metastatic mechanisms of CRC and potential targets for future therapeutic strategies. (4) Drug delivery and drug resistance reversal by exosomes: tumor drug resistance remains a significant challenge in treating CRC. As natural nanovesicles with favorable biocompatibility and targeting capabilities, exosomes can be engineered to serve as drug-delivery vehicles. When therapeutic molecules (e.g., miRNA inhibitors and chemotherapeutic agents) are loaded into exosomes, these nanoparticles can be accurately delivered to tumor cells, thereby overcoming drug resistance and enhancing therapeutic efficacy. Liang GF et al.\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e proposed an engineered exosome-targeted co-delivery system that combines miR-21 inhibitors and chemotherapeutic agents to reverse drug resistance in CRC. This innovative strategy offers novel approaches for overcoming tumor drug resistance. In summary, research on exosomes in CRC is advancing, encompassing various aspects, from molecular mechanisms to clinical applications. As research progresses, the potential of exosomes in diagnosis, therapy, and drug delivery will be increasingly realized.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Research hotspots\u003c/h2\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e4.3.1 The role of exosomes in the development of CRC\u003c/h2\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(1) Exosomes' immunomodulatory effects on the TME of CRC\u003c/span\u003e \u003c/p\u003e \u003cp\u003eExosomes play a dual role in the immune regulation of the TME in CRC. By mediating interactions between tumor cells and immune cells, stromal cells, and non-cellular components, exosomes can both promote immune escape and activate immune responses, profoundly affecting the progression of the tumor\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn terms of immunosuppression, exosomes can transfer bioactive molecules between different cell types in the TME, helping tumor cells evade immune surveillance and induce immune tolerance, ultimately promoting cancer progression\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. For example, exosomes derived from CRC carry tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which directly induces apoptosis of CD8⁺ T cells by binding to the surface receptors of T cells, thereby suppressing the immune response\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Exosomes secreted by CRC cells are rich in TGF-β1, which activates the TGF-β/Smad signaling pathway, upregulates the expression of Treg marker genes such as FoxP3 and CTLA-4, and induces Treg proliferation\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. CRC exosomes can also alter the differentiation direction of monocytes, promoting their transformation into myeloid-derived suppressor cells (MDSCs) and inhibiting the proliferation of immune cells and T cells\u003csup\u003e13\u003c/sup\u003e. CRC exosomes can also alter the differentiation direction of monocytes, promoting their transformation into MDSCs, thereby inhibiting the proliferation of immune cells and T cells\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Feng et al. demonstrate that CRC exosomes inhibit the NLRP3 pathway through TUT7-mediated accumulation of miR-1246, promoting the differentiation of M2-type TAMs, thereby enhancing the immunosuppressive environment\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Furthermore, CAFs transmit signals through exosomes and mediate the proteasomal degradation of MOB1A via the overexpression of WEE2-AS1, inhibiting the Hippo pathway and promoting the proliferation of CRC. In turn, tumor cells can reactivate CAFs, forming a self-sustaining pro-cancer environment\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. In CRC exosomes, circPACRGL regulates the TGF-βsignaling pathway through miR-142-3p/miR-506-3p, inducing the transformation of tumor-associated neutrophils from anti-tumor (N1) to pro-tumor (N2) phenotypes, thereby promoting the proliferation and metastasis of CRC cells\u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, exosomes not only exert immunosuppressive effects but can also activate immune responses, inhibiting tumor growth and metastasis. For instance, exosomes secreted by CRC cells contain miR-424, which can hinder the CD28-CD80/86 costimulatory pathway, activate immune checkpoints, and enhance immune responses, ultimately suppressing tumor growth\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e2. The role of exosomes in the metastasis and invasion of CRC\u003c/p\u003e\n\u003ch3\u003e1 Exosomes mediate angiogenesis in CRC\u003c/h3\u003e\n\u003cp\u003eAngiogenesis is the core event of tumor occurrence, progression, and metastasis. It promotes tumor growth by providing oxygen and nutrients and releasing pro-angiogenesis factors. Exosomes are closely related to angiogenesis and can promote the proliferation of CRC cells by regulating angiogenesis. Studies have shown that miRNA components, such as miR-21-5p, significantly enhance vascular permeability and neovascular density by inhibiting KRIT1 expression in endothelial cells, activating the β-catenin signaling pathway, and promoting the expression of VEGFA and CCND1\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Meanwhile, miR-1246 induced tubular differentiation of endothelial cells by activating the Smad1/5/8 pathway\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. However, miR-320d further improves angiogenesis efficiency by inhibiting GNAI1 and activating the JAK2/STAT3 cascade. In addition, circRNAs\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e, such as circTUBGCP4, activate the AKT signaling pathway by inhibiting miR-146b-3p, promoting the formation of vascular endothelial cells and tumor metastasis\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. CircPACRGL acts as a sponge for miR-142-3p and miR-506-3p, enhancing TGF-β1 expression by inhibiting the activity of these miRNAs, thereby promoting angiogenesis. In addition to non-coding RNAs, exosomes derived from CRC cells are enriched with proteins that promote angiogenesis. Exosomes were found to increase the expression of integrin (ITG) β1 and VEGFA in human umbilical vein endothelial cells, which are essential for blood vessel growth, maturation, and endothelial sprout formation25. In addition, B7-H3 has been identified as an integral component of CRC exosomes, promoting tumor angiogenesis and metastasis by activating the AKT1/mTOR/VEGFA signaling pathway\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Exosomes also fine-tune the blood vessel morphogenesis and angiogenesis process by influencing tip cell formation. These findings highlight the key role of exosomes in regulating tumor angiogenesis and provide a theoretical basis for developing novel anti-angiogenic therapeutic strategies targeting exosomes.\u003c/p\u003e\n\u003ch3\u003e2 Exosomes promote EMT in CRC\u003c/h3\u003e\n\u003cp\u003eEMT is a core biological process in CRC metastasis, characterized by the down-regulation of epithelial markers (such as E-cadherin) and up-regulation of mesenchymal markers (such as N-cadherin and vimentin). It was accompanied by a loss of cell polarity and increased aggressiveness. Exosomes induce EMT by delivering functional RNAs and proteins, significantly enhancing the migration and metastasis ability of CRC cells. Studies have shown that the CRC-derived exosome miR-106b-3p targets the tumor suppressor gene DLC-1, activates the EMT program, and promotes lung metastasis\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Similarly, exosome miR-335-5p significantly enhances migration in both in vitro and in vivo models by inhibiting RASA1 expression, activating the RAS signaling pathway, and inducing EMT phenotype\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. In addition, non-coding RNAs play a key role in exosome-mediated EMT. For instance, exosomal lncRNA 91H remodels the actin network and enhances CRC cell migration by binding to the cytoskeletal regulatory protein ARPC5\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. CircCSPP1 acts as a competitive endogenous RNA that binds to miRNA and promotes COL1A1 expression, thereby promoting EMT and liver metastasis in CRC cells\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. At the protein regulatory level, exosomal ADAM17 accelerates EMT-related metastasis by cutting the extracellular domain of E-cadherin, destroying intercellular adhesion connections\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. In addition, exosomes indirectly regulate EMT processes by remodeling the TME. Studies have demonstrated that exosomes can induce M2 macrophage polarization, activate the PI3K/AKT signaling pathway, and synergically promote EMT and angiogenesis, thus forming a positive feedback loop that facilitates metastasis\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. As a core regulator of the TME, exosomal LINC00355 secreted by CAFs releases adaptor proteins through competitive binding to miR-34b-5p, thereby enhancing chemotherapy resistance and accelerating the EMT process\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Moreover, hypoxic conditions within the TME stimulate CRC cells to release exosomes rich in Alu RNA, which activate the NLRP3 inflammasome, promote IL-1β secretion, and drive the expression of EMT-related genes via an NF-κB-dependent mechanism, creating a pro-metastatic inflammatory cascade\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e3 Exosomes promote the formation of PMN and organ metastasis in CRC\u003c/h3\u003e\n\u003cp\u003eExosomes play a key role in the formation of PMN and organ metastasis of CRC. First, exosomes drive metastasis targeting through ITG-mediated organotaxis. Hoshino A et al. revealed that ITGα6β4 and ITGα6β1 were mainly present in pulmonary exosomes, while ITGαvβ5 was primarily present in hepatic exosomes. ITG activates fibroblasts through the nuclear factor κB signaling pathway and induces high levels of pro-inflammatory cytokine production, triggering PMN establishment in the liver and lungs\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. Second, exosomes reshape the microenvironment of the target organ through their contents. For example, miR-25-3p facilitates the metastasis of CRC cells by inhibiting KLF2/KLF4 in endothelial cells, reducing the expression of tight junction proteins(such as ZO-1 and occludin) and increasing vascular permeability\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. In addition, the B7-H3 protein carried by exosomes activates the AKT1/mTOR/VEGFA signaling pathway, promoting angiogenesis and providing nutritional support for metastasis\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. In terms of immune regulation, CRC-derived exosomes deliver miR-372-5p and miR-106b, inducing M2 macrophage polarization, promoting CXCL12 secretion, and activating the WNT/β-catenin pathway, thereby establishing an immunosuppressive microenvironment that supports tumor metastasis\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. In addition, exosomes also provide conditions for tumor cell invasion by degrading the extracellular matrix (ECM) of the target organ. Exosomal lncRNAs carried by exosomes promote fibroblast activation and ECM remodeling by activating TGF-β and other pathways to form loose matrix structures\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. In summary, exosomes coordinate the formation of PMN through multiple mechanisms, such as organ-specific targeting, angiogenesis, immune regulation, and ECM remodeling, providing the \"soil\" for CRC metastasis and ultimately promoting the organ metastasis of CRC.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e4.3.2 The application of exosomes in the diagnosis and prognosis of CRC\u003c/h2\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(1)Exosomal miRNAs\u003c/span\u003e \u003c/p\u003e \u003cp\u003eExosomal miRNAs show essential value in the early diagnosis and prognosis assessment of CRC. Studies indicate that miR-21 is significantly up-regulated in the serum exosomes of CRC patients and promotes tumor proliferation by inhibiting PDCD4 and other tumor suppressor genes\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e, with a diagnostic sensitivity of 75% and specificity of 84%\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. Han et al. \u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e also observed that miR-15b, miR-16, and miR-31 were notably up-regulated in the exosomes of CRC patients, and the combination of these miRNAs could significantly improve the accuracy of CRC diagnosis. MiRNAs such as miR-150-5p, miR-335-5p, miR-17-92, and miR-215 are closely associated with CRC invasion and metastasis, making them potential biomarkers\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Among these, the low expression of miR-150-5p correlates significantly with poor tumor differentiation, lymph node metastasis (LNM), and advanced TNM stage. The expression of miR-150-5p in CRC patients with LNM is approximately 2.4 times lower than in non-metastatic patients. However, after surgical resection of the tumor, the serum levels of miR-150-5p significantly increase, making it a valuable indicator for prognosis assessment and postoperative monitoring\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e. Another study found that low miR-193a and high let-7g expression patterns were strongly associated with shorter overall survival in CRC patients, suggesting their potential as biomarkers for relapse monitoring\u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e. Furthermore, exosomal miRNAs also reflect chemotherapy sensitivity. For instance, the expression levels of miR-92a-3p and miR-221-3p are significantly correlated with oxaliplatin resistance, with the AUC of predicted efficacy being 0.735 and 0.774, respectively\u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(2)Exosomal proteins\u003c/span\u003e \u003c/p\u003e \u003cp\u003eExosomal proteins have also proven to be valuable biomarkers for CRC. Studies reveal that the expression levels of exosomal proteins in the blood of CRC patients are markedly different from those in healthy controls. Proteins such as CD147, HSP60, and GPC1 in exosomes can serve as early diagnostic biomarkers for CRC. The expression of exosomal proteins is significantly increased in metastatic CRC patients, with these levels closely linked to tumor aggressiveness and metastatic potential. Sun et al.\u003csup\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e found that exosomal CPNE3 levels were significantly elevated in patients with advanced TNM stage or distant metastasis. The combined detection of exosomal CEA and CPNE3 showed a sensitivity of 81.2% and specificity of 84.8%, significantly outperforming single detections of either CEA or CPNE3. Moreover, patients with high CPNE3 expression exhibited lower disease-free survival and overall survival rates compared to those with low CPNE3 expression, highlighting the potential of CPNE3 as a biomarker for early diagnosis and prognosis assessment. Additionally, exosomal PD-L1 promotes immune escape by inhibiting T-cell activity, suggesting its use as a biomarker for poor prognosis. Variations in PD-L1 levels after surgery or chemotherapy can also help monitor the risk of recurrence\u003csup\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(3)Exosomal lncRNAs\u003c/span\u003e \u003c/p\u003e \u003cp\u003eExosomal lncRNAs are tissue-specific and exhibit stable expression across various tissues. Studies have demonstrated that lncRNA CRNDE-h is significantly upregulated in serum exosomes of CRC patients, and its diagnostic value surpasses that of the traditional biomarker CEA. When combined with CEA, the diagnostic efficiency improves, with an AUC of 0.91\u003csup\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e. lncRNA-ADAMTS9-AS1, an antisense lncRNA, is dysregulated in multiple tumors and inhibits CRC progression by interfering with the Wnt/β-catenin signaling pathway, making it a potential diagnostic biomarker\u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e. Furthermore, the overexpression of lncRNA CRNDE-h is positively associated with LNM and distant metastasis in CRC, suggesting its value in prognosis evaluation\u003csup\u003e48\u003c/sup\u003e. Another example is lncRNA PCGEM1, which is significantly upregulated in CRC. When combined with miR-152-3p, it has been shown to improve diagnostic accuracy, suggesting its potential as a novel biomarker for prognostic evaluation\u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(4)Exosomal circRNAs\u003c/span\u003e \u003c/p\u003e \u003cp\u003eCircRNAs possess a covalent closed-loop structure, making them stable and highly conserved. They are abundantly expressed in eukaryotic tissue development, and the expression profiles of circRNAs in exosomes from tumor patients differ significantly from those in healthy individuals. Their high abundance, specificity, and stability make them promising non-invasive biomarkers for liquid biopsy. For instance, circRNA-0004771 is significantly upregulated in the serum exosomes of CRC patients, with an AUC of 0.88 for distinguishing CRC from healthy controls and 0.816 for distinguishing stage I and II patients from other benign intestinal diseases\u003csup\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e. This shows better diagnostic sensitivity and specificity than traditional biomarkers. CircRNAs also promote metastasis by mediating communication between tumor cells and the TME. For example, exosomal circ-0084043 secreted by CAFs activates endothelial cells to promote angiogenesis through the miR-153-5p/SNAI1 axis, which is linked to CRC liver metastasis\u003csup\u003e[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/sup\u003e. Circ-FMN2 is overexpressed in the serum and exosomes of CRC patients, and its levels correlate positively with the LNM and TNM stages. Circ-FMN2 accelerates CRC cell proliferation and metastasis while inhibiting apoptosis through the miR-338-3p/MSI1 axis, making it a potential specific biomarker for CRC and a therapeutic target for clinical applications\u003csup\u003e[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]\u003c/sup\u003e. Furthermore, exosomal circRNAs are involved in the mechanism of chemotherapy resistance. For example, the high expression of circ-0004771 in CRC patients is associated with oxaliplatin resistance, with its levels predicting treatment response and survival outcomes\u003csup\u003e[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec24\" class=\"Section3\"\u003e \u003ch2\u003e4.3.3 The application of exosomes in the treatment of CRC\u003c/h2\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(1) Drug delivery\u003c/span\u003e \u003c/p\u003e \u003cp\u003eExosomes, as natural nanocarriers, have significant advantages in CRC drug delivery. Their lipid bilayer structure and inherent biocompatibility enable efficient passage across physiological barriers, such as gastrointestinal mucosa and vascular endothelium, allowing targeted drug delivery to specific sites. Studies have demonstrated that exosomes derived from mesenchymal stem cells retain structural stability by carrying transmembrane proteins (e.g., CD9 and CD63), which protect the drugs from degradation within the circulatory system, thus enhancing delivery efficiency\u003csup\u003e[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]\u003c/sup\u003e. Furthermore, exosomes can cross the blood-brain barrier, holding promise for targeted treatment of CRC metastases in the brain. To improve their targeting specificity, exosomes can also be engineered through chemical modifications or gene-editing techniques. For instance, modifying ligands of tumor-associated antigens (such as CEA or EpCAM) on the surface of exosomes enables them to target and accumulate on CRC cell surfaces accurately, thus minimizing off-target effects on healthy tissues. Exosomes secreted by CRC cells naturally exhibit homing properties, further enhancing their targeting capabilities. A33-positive exosomes, for example, can specifically recognize CRC cell surface antigens, resulting in a significantly higher concentration of Adriamycin at tumor sites than in normal tissues, thereby improving tumor-targeting efficiency. When the A33 antibody and exosome complex (A33Ab-US-Exo/Dox) modified by magnetic nanoparticles was used, the uptake efficiency of tumor cells was improved, and the cardiac toxicity was significantly reduced\u003csup\u003e[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]\u003c/sup\u003e. Regarding multi-drug collaborative delivery, exosomes can simultaneously carry chemotherapy drugs, nucleic acid drugs, and protein drugs, thus enabling a multi-mechanism collaborative therapeutic approach. Studies have shown that exosomes loaded with oxaliplatin and miR-34a significantly inhibit CRC cell proliferation and migration by regulating the Wnt/β-catenin pathway\u003csup\u003e[\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]\u003c/sup\u003e. Dual-drug co-loaded systems (e.g., Farnyl and paclitaxel) significantly reduce CRC cell activity by blocking the cell cycle and inhibiting microtubule depolymerization through synergistic mechanisms\u003csup\u003e[\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]\u003c/sup\u003e. Another research team co-loaded doxorubicin and photosensitizer in HCT116 cell-derived exosomes and developed nanoprobes with chemotherapy, photodynamic therapy, and real-time monitoring functions, which showed more substantial tumor inhibition effects and lower systemic toxicity in vivo experiments\u003csup\u003e[\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]\u003c/sup\u003e. Compared with synthetic nanoparticles, exosomes have low immunogenicity and long-term cycling properties, and their surface membrane proteins can reduce the risk of recognition by the immune system, thereby extending the cycle time in vivo. Studies have shown that hybrid exosomes formed by fusing mesenchymal stem cell-derived exosomes with folate-targeted liposomes show significantly extended tumor retention time in CT26 CRC models. In vivo experiments confirmed that the tumor growth inhibition rate of the hybrid exosomes treatment group was 2.8 times higher than that of traditional liposomes\u003csup\u003e[\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]\u003c/sup\u003e. This finding aligns with nanoparticle engineering research, which indicates that CD47 modification can extend nanoparticle circulation time by up to sixfold. Exosomes naturally carry CD47 and other bioactive molecules, resulting in a longer circulation time than conventional PEG-liposomes\u003csup\u003e[\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]\u003c/sup\u003e. Exosomes present an innovative strategy for precision drug delivery in CRC, offering natural targeting, high drug loading capacity, and low toxicity. They hold great potential for combination therapy and individualized medicine in the future.\u003c/p\u003e\u003cp\u003e\u003cspan\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e2. Mediating tumor drug resistance\u003c/span\u003e\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eThe mechanism of exosome-mediated CRC resistance is a complex process involving multi-dimensional regulation. First, exosomes regulate drug efflux mechanisms and participate in the formation of drug resistance. By actively excreting cytotoxic drugs, exosomes significantly reduce intracellular drug concentration and form a protective barrier by wrapping chemotherapy drugs to weaken the killing effect of drugs. Secondly, resistant cells transmit resistance signals to sensitive cells through exosomes. For example, the exosomes of cetuximab-resistant CRC cells carry lncRNA-UCA1, which up-regulates the expression of myosin Ⅵ by binding miRNA-143, inducing sensitive cells to acquire proliferation ability and drug-resistant phenotype\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e]\u003c/sup\u003e. In addition, stromal cell-derived exosomes can induce drug resistance. For example, exosomes secreted by CAFs carry miRNA-92a-3p and miRNA-196b-5p, which induce sensitive cells to acquire stem-like phenotype and inhibit apoptosis, thereby enhancing chemotherapy resistance\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e]\u003c/sup\u003e. It is worth noting that CRC-resistant cell lines are associated with EMT, and molecules such as related proteins carried by stromal exosomes can induce EMT in CRC cells and reduce chemotherapy sensitivity\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e]\u003c/sup\u003e. In recent years, siRNA-mediated gene silencing techniques have shown significant potential in reversing chemotherapy resistance in CRC by targeting key resistance genes. For example, targeted silencing of VEGF by siRNA significantly inhibits CRC cell proliferation. Studies have shown that siRNA silencing SEMA4D gene combined with 5-FU on SW480 cells can increase the apoptosis rate and induce 5-FU resistance in CRC cells through caspase cascade reaction\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e65\u003c/span\u003e]\u003c/sup\u003e. Exosomes are key agents driving CRC resistance through multiple mechanisms, and intervention strategies targeting the functional molecules carried by them may provide new directions for reversing chemotherapy resistance.\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e3. Immunotherapy\u003c/span\u003e\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eExosomes play a complex and bidirectional role in CRC immunotherapy, both promoting tumor immune evasion and serving as potential tools to enhance immune responses. On the one hand, exosomes inhibit anti-tumor immunity through a variety of mechanisms. They carry immune checkpoint molecules, such as PD-L1, that directly inhibit T cell activation and function and induce T cell depletion. At the same time, TGF-\u0026beta; and other immunosuppressive factors were transported to promote the expansion of Tregs and further inhibit the activity of effector T cells. In addition, exosomes impair T-cell initiation by delivering functional molecules that inhibit dendritic cell (DC) maturation and antigen presentation. On the other hand, exosomes also have potential as immunotherapeutic vectors. By genetically engineering or loading specific molecules, exosomes can be designed as tools to enhance anti-tumor immune responses. Exosomes loaded with tumor-associated antigens can be used as vaccines to stimulate the body to produce specific cytotoxic T lymphocyte responses, thereby improving the immune surveillance and clearance of CRC. In addition, exosomes can also carry co-stimulatory molecules or cytokines that enhance the antigen presentation capacities of DCs and T-cell activation. For example, Me49-DC-Exo has shown antitumor effects in CRC models by delivering an antigenic component of the parasite and stimulating a T-cell immune response\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e66\u003c/span\u003e]\u003c/sup\u003e. Furthermore, exosomes can be used to provide immune checkpoint inhibitors, and experimental studies have shown that exosomes carrying PD-L1 siRNA and CTLA-4 siRNA can effectively inhibit tumor growth and enhance anti-tumor immune responses in tumor-bearing mouse models\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e67\u003c/span\u003e]\u003c/sup\u003e. Therefore, an in-depth understanding of the mechanism of exosomes in the CRC immune microenvironment and rational use of their properties are expected to develop more effective CRC immunotherapy strategies.\u003c/p\u003e\n\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\n \u003ch2\u003e4.4 Emerging frontiers\u003c/h2\u003e\n \u003cp\u003eIn recent years, exosomes, as a crucial medium for intercellular communication, have demonstrated substantial potential in the fundamental mechanistic research of CRC, the advancement of liquid biopsy technologies, and the development of targeted therapies. Moving forward, research in this field is expected to focus on three primary trends: the synergy between multi-omics approaches and artificial intelligence (AI) to drive the clinical transformation of liquid biopsies, the precise targeting of exosome-mediated metastasis and immune escape mechanisms, and the integration of engineered exosomes with nanotechnology to facilitate innovations in drug delivery systems. The realization of these trends will not only depend on integrating interdisciplinary technologies but also require overcoming technical challenges related to standardized production and clinical translation, ultimately establishing a new paradigm for CRC precision medicine.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(1) From biomarker discovery to clinical translation: multi-omics and AI collaboratively driving liquid biopsy 2.0.\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003eExosomes, which carry nucleic acids, proteins, lipids, and other bioactive substances, have become a new \u0026quot;information treasure\u0026quot; in liquid biopsy. Compared with traditional circulating tumor DNA or circulating tumor cells, exosomal biomarkers have higher stability and tissue specificity. They can more sensitively reflect the molecular heterogeneity and dynamic evolution of CRC. However, it is difficult for single omics data to analyze the complex functions of exosomes comprehensively, so multi-omics integration and AI algorithm optimization will become the core strategy to improve diagnostic efficiency. The combined application of multiple omics (including genomics, transcriptomics, proteomics, and metabolomics) will reveal the synergistic mechanism of DNA mutations, non-coding RNAs, and transmembrane proteins in CRC exosomes. The application of AI technology in this area focuses on data dimensionality reduction and model optimization: deep learning algorithms can build multimodal predictive models by integrating exosomal miRNA profiles, metabolomics data, and clinicopathological features.\u003c/p\u003e\n \u003cp\u003eTherefore, future liquid biopsy technologies based on exosomes will go beyond incremental advancements over traditional methods. By integrating multi-omics and AI, they are poised to bring a transformative shift in the field.\u003c/p\u003e\n \u003cp\u003eThis transformation will enable \u0026quot;Liquid Biopsy 2.0\u0026quot; for CRC screening and dynamic monitoring, enhancing early diagnosis and improving patient survival outcomes. This advanced method of liquid biopsy holds the potential to significantly enhance early CRC detection and ultimately improve patients\u0026apos; prognosis.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(2) From mechanism analysis to precise intervention: targeting exosome-mediated metastasis and immune escape\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003eCRC metastasis and immune escape are the leading causes of treatment failure. Exosomes play an essential role in the communication between tumor cells and are involved in constructing the metastasis microenvironment and the induction of immunosuppression. An in-depth analysis of the mechanism of exosomes in CRC metastasis and immune escape will provide new ideas for developing targeted drugs or combination therapy. For example, inhibitors targeting exosome secretion, such as GW4869, could reduce exosome release, thereby inhibiting tumor metastasis and immune evasion. When combined with oxaliplatin, these inhibitors could enhance the sensitivity of CRC cells to chemotherapy\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e68\u003c/span\u003e]\u003c/sup\u003e. In addition, blockers targeting exosomal target cell interactions can also be developed, for example, by blocking the exosome-mediated \u0026quot;don\u0026apos;t eat me\u0026quot; signal through anti-CD47 antibodies, thereby inhibiting the binding of exosomes to target cells and reducing their biological effects. Furthermore, exosome inhibitors can be combined with immune checkpoint inhibitors, enhancing anti-tumor immune response and overcoming immune resistance.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e(3) From basic research to engineering applications: the fusion of engineered exosome vectors and biomimetic nanotechnology\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003eNatural exosomes are known for their excellent biocompatibility and inherent targeting capabilities; however, their drug-carrying capacity remains limited. By genetically engineering exosomes to express specific targeting ligands or to load therapeutic drugs, the targeting and efficacy of drugs can be improved. Moreover, the integration of engineered exosomes with biomimetic nanotechnology offers a promising avenue to overcome the limitations of current drug delivery systems, thus improving drug delivery efficiency and safety. For example, exosomes can be encapsulated in liposomes to form a new nano-drug delivery system. This system combines the targeting of natural membrane proteins with the high drug load of artificial carriers and can also improve the stability and bioavailability of drugs\u003csup\u003e60\u003c/sup\u003e. In addition, pH-sensitive exosomes release siRNA in the acidic TME or use heat-sensitive hydrogels to control the slow-release rate\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e69\u003c/span\u003e]\u003c/sup\u003e. In the future, the fusion of engineered exosome carriers and biomimetic nanotechnology is expected to improve the targeting of drugs, which will provide new possibilities for the personalized precision treatment of CRC.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"5 Innovation and limitation","content":"\u003cp\u003eIn this study, visualization tools such as CiteSpace, VOSviewer, RStudio, GraphPad, and SciExplorer were used to conduct an in-depth analysis of the research trends in the field of exosomes in CRC. CiteSpace has outstanding performance in co-citation analysis and knowledge graph construction, which can effectively outline the development track of this research domain. VOSviewer uses advanced web visualization technology to show research topics' relationships and knowledge structure clearly. RStudio, GraphPad, and SciExplorer provide robust support for data analysis and the generation of customized charts. By integrating these tools, this study can dig deep into the bibliometric data and reveal the research trends, hotspots, and future directions in this field. In addition to the traditional hotspot analysis, this study innovatively incorporates Burst Detection and Topic Modeling. The former is used to identify emerging research themes in a specific period, while the latter extracts potential themes and trends from massive literature to provide prospective guidance for future research. However, there are several limitations in this study. First, the inclusion of only the WOSCC database may lead to the omission of studies from other vital databases and non-English literature (e.g., Chinese core journals), thus affecting the comprehensiveness of the analysis results. Furthermore, the limitations inherent in citation analysis should be acknowledged. Although the number of citations can reflect a paper's influence, it does not fully represent its quality or innovation. Highly cited papers may also be subject to controversies or contain errors. Lastly, as the field of exosome research in CRC is rapidly evolving, with an increasing volume of literature, the analysis results may lag behind current developments and fail to capture the latest research progress fully. Therefore, future studies should consider incorporating a broader range of data sources and adopting updated analytical methodologies to obtain a more comprehensive understanding of the dynamic evolution of this field.\u003c/p\u003e"},{"header":"6 Conclusion","content":"\u003cp\u003eThe bibliometric analysis of exosomes in CRC reveals a notable growth trend in recent years, underscoring the academic community's growing attention to the role of exosomes in the pathogenesis, diagnosis, and treatment of CRC. China contributes to approximately half of the global research output in this field; however, despite strong domestic academic collaboration, international cooperation remains limited, which restricts the global impact of these studies. Currently, exosome research focuses on the role of non-coding RNAs, their application as biomarkers, the regulation of the TME, and the innovation of drug delivery systems. These studies not only provide new perspectives for early CRC diagnosis and personalized treatments but also offer valuable insights into future research directions. With the integration of multi-omics technologies and AI, the application of exosomes in liquid biopsy holds significant promise. Future research should prioritize strengthening international collaborations to facilitate the translation of basic research into clinical applications, ultimately achieving breakthroughs in CRC precision medicine.\u003c/p\u003e \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTop 10 countries with the highest number of publications related to exosomes in CRC.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCountry/region\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eArticle counts\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCentrality\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePercentage\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal citations\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAverage citation\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCHINA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e895\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e52.49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33570\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.96%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eITALY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.69%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIRAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.51%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2422\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGERMANY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.16%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e53.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJAPAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.11%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4658\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66.54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSOUTH KOREA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.58%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2611\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAUSTRALIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.34%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e79.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSPAIN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.23%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eENGLAND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.99%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2443\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTop 10 productive institutions contributing to research on exosomes in CRC.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInstitution\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of studies\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal citations\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAverage citation\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFudan University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShanghai Jiao Tong University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2492\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNanjing Medical University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSun Yat-Sen University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1728\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZhengzhou University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCentral South University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1261\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShandong University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1559\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZhejiang University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina Medical University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e765\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSouthern Medical University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1793\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTop 10 productive journals and co-cited journals related to exosomes in CRC.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eJournal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eArticle counts\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIF\u003c/p\u003e\n \u003cp\u003e(2024)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eJCR\u003c/p\u003e\n \u003cp\u003e(2024)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCited Journal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCo-citations\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIF\u003c/p\u003e\n \u003cp\u003e(2024)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eJCR\u003c/p\u003e\n \u003cp\u003e(2024)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCancers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCancer Research\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInternational Journal of Molecular Sciences\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePLOS ONE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1047\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrontiers in Oncology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNature\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e965\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMolecular Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOncotarget\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e959\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOncotarget\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMolecular Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e942\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCell\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e935\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrontiers in Cell and Developmental Biology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eScientific Reports\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e925\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJournal of Extracellular Vesicles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNature Communications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e884\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eScientific Reports\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInternational Journal of Molecular Sciences\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e868\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCancer Cell International\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProceedings of the National Academy of Sciences of the United States of America\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e854\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTop 10 productive authors and co-cited authors related to exosomes in CRC.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAuthor\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCounts\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCo-cited author\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCitations\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimpson R.J.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThery C.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e358\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGreening D.W.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKalluri R.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e331\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWang C.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZhang Y.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e286\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDu L.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLi Y.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e258\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLi J.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHoshino A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e242\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRai A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSiegel R.L.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e234\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCoffey R.J.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eValadi H.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e232\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJi H.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLi J.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e232\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eXu W.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVan N.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e208\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZhang W.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeinado H.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTop 10 co-citation references related to exosomes in CRC\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTitle\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eJournal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eauthor(s)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal citations\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThe biology, function, and biomedical applications of exosomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eSCIENCE\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKalluri R.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e186\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eMOLECULAR CANCER\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHu J.L.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMinimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eJOURNAL OF EXTRACELLULAR VESICLES\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWelsh J.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCarcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eTHERANOSTICS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRen J.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShedding light on the cell biology of extracellular vesicles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eNATURE REVIEWS MOLECULAR CELL BIOLOGY\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVan Niel G.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e115\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eNATURE COMMUNICATIONS\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZeng Z.C.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e104\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumour exosome integrins determine organotropic metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eNATURE\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHoshino A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLong noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eINTERNATIONAL JOURNAL OF CANCER\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeng X.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p-TGF-\u0026beta;1 axis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eMOLECULAR CANCER\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShang A.Q.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpecificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eNATURE CELL BIOLOGY\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMathieu M.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eHigh-frequency keywords associated with exosomes in CRC.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKeyword\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCounts\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKeyword\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCounts\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecolorectal-cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e637\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ediagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eextracellular vesicles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e509\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehepatocellular-carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e279\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eepithelial-mesenchymal transition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e109\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ebiomarkers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003echemoresistance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eprogression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eserum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emicroRNAs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eresistance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eproliferation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003estem-cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einvasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eprognosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etumor microenvironment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eprostate-cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eliquid biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eangiogenesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCRC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Colorectal Cancer\u003c/p\u003e\n\u003cp\u003eTME \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Tumor Microenvironment\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePMN \u0026nbsp; \u0026nbsp; \u0026nbsp; Pre-metastatic Niche Formation\u003c/p\u003e\n\u003cp\u003eWOSCC \u0026nbsp; \u0026nbsp;Web of Science Core Collection\u003c/p\u003e\n\u003cp\u003eMCP \u0026nbsp; \u0026nbsp; \u0026nbsp; Multinational Publications\u003c/p\u003e\n\u003cp\u003eSCP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Single-country Publications\u003c/p\u003e\n\u003cp\u003eIF \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Impact Factor\u003c/p\u003e\n\u003cp\u003eEMT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Epithelial-mesenchymal Transition\u003c/p\u003e\n\u003cp\u003eCAFs \u0026nbsp; \u0026nbsp; \u0026nbsp; Cancer-associated Fibroblasts\u003c/p\u003e\n\u003cp\u003eTAMS \u0026nbsp; \u0026nbsp; \u0026nbsp;Tumor-associated Macrophages\u003c/p\u003e\n\u003cp\u003eTRAIL \u0026nbsp; \u0026nbsp; \u0026nbsp;Tumor Necrosis Factor-related Apoptosis-inducing Ligand\u003c/p\u003e\n\u003cp\u003eMDSCs \u0026nbsp; \u0026nbsp; Myeloid-derived Suppressor Cells\u003c/p\u003e\n\u003cp\u003eITG \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Integrin\u003c/p\u003e\n\u003cp\u003eLNM \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Lymph Node Metastasis\u003c/p\u003e\n\u003cp\u003eDC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Dendritic cell\u003c/p\u003e\n\u003cp\u003eAI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Artificial Intelligence\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003eThanks to the editors and reviewers for their hard work and important comments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was supported by the National Natural Science Foundation of China (No. 82204800), the National Outstanding Youth Science Fund Project of the National Natural Science Foundation of China (No. 8190150554), the Seventh Batch of National Traditional Chinese Medicine Experts\u0026apos; Academic Experience Inheritance Program, National Administration of Traditional Chinese Medicine (Document No.76,2022), the Graduate Research and Innovation Projects of Jiangsu Province (SJCX241010, SJCX240944), the Open Project of Zhenjiang Traditional Chinese Medicine Spleen and Stomach Disease Clinical Medicine Research Center (Zhenjiang Hospital Affiliated to Nanjing University of Chinese Medicine, Zhenjiang Hospital of Traditional Chinese Medicine) (No.SSPW2023-KF07), the Jiangsu Provincial Administration of Traditional Chinese Medicine Program (No. MS2023014), and the Jiangsu Provincial Medical Key Discipline (Laboratory) (No. ZDXYS202208).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eML and YJ : Conceptualization, Investigation, Software, Visualization, Writing-original draft, Writing-review \u0026amp; editing. LS: Writing-original draft, Software, Writing-review \u0026amp; editing, Visualization. CX: Writing-review \u0026amp; editing, Software, Writing-original draft. JG: Writing-review \u0026amp; editing, Software, Writing-original draft. MY: Writing-review \u0026amp; editing, Software. WL: Writing-review \u0026amp; editing. QS: Writing-review \u0026amp; editing. JQ: Writing-review \u0026amp; editing.All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eResearch data are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish declaration:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate declaration:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMorgan E, Arnold M, Gini A, et al. 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Potential of Exosomes as Multifunctional Nanocarriers for Targeted Drug Delivery. \u003cem\u003eMol Biotechnol\u003c/em\u003e.2024;doi:10.1007/s12033-024-01268-6\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"colorectal cancer, exosome, bibliometric analysis, visualization, R-bibliometrix, research trends","lastPublishedDoi":"10.21203/rs.3.rs-6450425/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6450425/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eColorectal cancer (CRC) is one of the most frequent malignant tumors in the world. Its pathogenesis is complex and prone to metastasis and relapse, so novel diagnostic biomarkers and therapeutic strategies are urgently needed. As nanoscale vesicles secreted by cells, exosomes carry bioactive molecules, including nucleic acids, proteins, and lipids, and play a key role in regulating the tumor microenvironment (TME), forming the pre-metastatic niche (PMN) and contributing to drug resistance in CRC. Through bibliometrics, this study reviewed research progress, cooperation networks, and frontiers of exosomes in the field of CRC to fill the gap of systematic analysis and provide a theoretical basis for future research.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBased on the Web of Science Core Collection (WOSCC) database, the relevant literature on exosomes in the field of CRC from 2003 to 2024 was searched. Tools such as CiteSpace, VOSviewer, RStudio, GraphPad, and SciExplorer are used to visually analyze publishing trends, national contribution, institutional cooperation, author influence, journal distribution, co-citation network, and keyword co-occurrence to predict future research hotspots.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThis study included 1705 articles from 76 countries, involving 9113 authors and 2240 institutions, and published in 513 journals. The analysis showed that the research on exosomes in CRC showed a continuous upward trend, especially in recent years, indicating that this field has received more and more attention and in-depth research. China leads the world in terms of research output (\u0026gt;\u0026thinsp;50%), but the number of citations per article is relatively low, while the United States stands out regarding citation impact and academic centrality. China's domestic academic cooperation is relatively active, but international cooperation must be strengthened. Cancers is the most widely published journal in the field. Simpson R.J. tops the list of authors with 16 papers, and Thery C. is the most frequently cited author. In addition to \"colorectal cancer\" and \"extracellular vesicles,\" \"metastasis,\" \"biomarker,\" and \"progression\" are also popular keywords. It reflects that the research mainly focuses on the role of exosomes in the occurrence, development, diagnosis, prognosis, and treatment of CRC. Emerging research trends are gradually shifting from basic biological mechanisms to clinical applications and technological innovations, emphasizing the potential value of exosomes in the early diagnosis of CRC, therapeutic monitoring, and individualized therapy.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThrough bibliometric analysis, this study reviewed the current research status and development trend of exosomes in CRC. Future studies should focus on strengthening international cooperation to promote the effective transformation of basic research into clinical application to achieve breakthroughs in CRC precision medicine.\u003c/p\u003e","manuscriptTitle":"Global trends and future perspectives on exosomes in colorectal cancer: a comprehensive bibliometric analysis (2003-2024)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-03 16:53:55","doi":"10.21203/rs.3.rs-6450425/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ecd2e5f5-3b06-4677-80c3-5d3d40fbc4b7","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-18T10:38:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-03 16:53:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6450425","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6450425","identity":"rs-6450425","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}