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Tracing the cellular origins and unraveling the heterogeneity of extracellular vesicles in cancer research: From bulk to single-vesicle analysis

Kezhen Yi1# ,  Xiaodan Xi1,2# ,  Cheng Wang3# ,  Qiaoyun Liu4# ,  Wei Zhong1 ,  Fei Long1 ,  Yike Wang5 ,  Yuan Rong1* ,  Min Xie5* ,  Fubing Wang6,7,8*
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1 Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
2 Department of Clinical Laboratory, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3 Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
4 Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Wuhan, Hubei, China
5 College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, China
6 Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
7 Institute of Clinical Molecular Diagnostics, Wuhan University, Wuhan, China
8 Hubei International Science and Technology Cooperation Base for Digital and Intelligent Molecular Diagnostics, Wuhan, China
BMT, 174 https://doi.org/10.12336/bmt.25.00174
Submitted: 7 September 2025 | Revised: 31 July 2026 | Accepted: 13 August 2026 | Published: 13 October 2026
© 2026 by the Author(s). Licensee Biomaterials Translational, USA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 (CC BY-NC-SA 4.0) (https://creativecommons.org/licenses/by-nc-sa/4.0/deed.en)
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Abstract

Extracellular vesicles (EVs) are released by diverse cell types and tissues and carry molecular cargo that reflects the biological states of their parental cells. This source diversity generates marked EV heterogeneity, creating both opportunities and challenges for cancer liquid biopsy. In this review, we distinguish EV characterization, heterogeneity analysis, and origin tracing. Source-controlled EV characterization using cultured cells, animal models, patient-derived organoids, and organ-on-chip systems provides reference signatures for understanding EV dynamics and source-associated molecular features. Bulk EV profiling based on RNA sequencing, proteomics, lipidomics, or metabolomics can support population-level source inference when combined with tissue-specific markers, single-cell atlases, and deconvolution algorithms, but may obscure rare tumor-derived EV subpopulations. Single-vesicle technologies, including nano-flow cytometry, super-resolution microscopy, Raman-based detection, microfluidic assays, digital platforms, and proximity-based barcoding, further resolve EV subpopulations and enable marker co-localization analysis for source assignment. Mechanistically, EV heterogeneity arises from differences in cellular origin, vesicle biogenesis, selective cargo sorting, tumor microenvironmental conditions, and therapy-induced remodeling. We discuss the applications, advantages, and limitations of these strategies in cancer research, with emphasis on early diagnosis, prognostic evaluation, and dynamic treatment monitoring. We also highlight key biological and technical challenges, including the low abundance of tumor-origin EVs, non-EV particle contamination, marker ambiguity, pre-analytical variability, incomplete reference atlases, and limited reproducibility across platforms. Integration of bulk and single-vesicle data with spatial omics, imaging, and clinical variables may further strengthen source attribution and support scalable translation across cancer types and settings. Clinically reliable EV tracing will require standardization guided by the Minimal Information for Studies of EVs recommendations, rigorous particle characterization, combinatorial source markers, orthogonal validation, and independent cohort evaluation. A source-resolved EV tracing framework may therefore improve the biological interpretability, analytical reliability, and clinical value of EV-based cancer liquid biopsy.

Keywords
Extracellular vesicles
Origin tracing
Heterogeneity
Single-vesicle analysis
Liquid biopsy
Cancer
Funding
This study was funded by the National Natural Science Foundation of China (12375349), the Innovation Group of Hubei Provincial Natural Science Foundation (2022CFA005), the Clinical Key Project of the Science and Technology Achievement Transformation Fund (2022CGZH-ZD004), the Basic and Clinical Medical Research Joint Fund of Zhongnan Hospital and Wuhan University (ZNLH202209), and the Translational Medicine and Interdisciplinary Joint Fund of Zhongnan Hospital (ZNJC202210).
Conflict of interest
The authors declare no conflicts of interest.
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