Abstract
Extracellular vesicles (EVs) encompass a multitude of lipid bilayer-delimited particles, of which exosomes are the most widely studied. Bidirectional cell–cell communications via EVs have a pivotal role in the physiology of multicellular organisms. EVs carry biological cargoes (including proteins, RNA, DNA, lipids and metabolites) capable of mediating a range of pleiotropic cellular functions. Over the past decade, EVs released by cancer cells (onco-EVs) have been shown to promote cancer progression including tumour outgrowth and metastatic dissemination. Furthermore, the innate ability of EVs to protect vulnerable molecular cargoes (such as RNA, DNA or proteins) from enzymatic degradation, their presence in most biofluids and the ability to transverse biological barriers to reach distant organs make them ideal targeted drug delivery systems, including in patients with cancer. Many of these properties also support investigations of EVs as biomarkers with potential roles in both diagnosis and treatment monitoring. In this Review, we describe advances in the development of EVs as cancer therapeutics or biomarkers, including cancer vaccines, targeted drug delivery systems and immunotherapies, as well as potential roles in early cancer detection, diagnosis and clinical management. We also describe the potential of emerging technologies to support further discoveries as well as the clinical translation of EVs into diagnostic and therapeutic clinical tools. We highlight the potential of single-EV and onco-EV detection and discuss how advances in multi-omic and artificial intelligence-enabled integration are providing new biological insights and driving clinical translation.
Key points
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Extracellular vesicles (EVs) are directly released from cancer cells and thus provide a direct but accessible source of information on tumour biology with potential for implementation as biomarkers to guide the management of patients with cancer.
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EVs released from cancer cells are able to interact with the tumour microenvironment and with non-malignant cells at distant anatomical locations, thus enabling the progression and metastatic dissemination of cancer.
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EV-mediated cell–cell communication and cargo transfer between tumour and non-tumour cells are involved in all stages of cancer — from development to metastatic dissemination and modulation of the host immune response.
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EVs can be engineered and have potential clinical utility as next-generation drug delivery platforms for cancer therapeutics as well as a potential role as cancer vaccines or for the delivery of immunotherapies.
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Thus far, the clinical development and implementation of EV-based biomarkers or therapeutics have been limited owing to various technical challenges.
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Technological advances and improved integration of omics and other technologies are expected to continue to advance the clinical implementation of therapeutics or diagnostics involving EVs.
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Acknowledgements
D.W.G.’s laboratory is supported by research funds from the National Health and Medical Research Council (NHMRC; MRF2015523 and APP1141946), National Heart Foundation (NHF; 105072), Helen Amelia Hains Fellowship (D.W.G.) and Department of Defense (PR230065). R.X. is supported by research funds from CASS Foundation (10380), Bethlehem Griffiths Research Foundation (2302) and Monash Future Leadership Fellowship (R.X.). The Baker Heart & Diabetes Institute acknowledges support by the Victorian State Government Operational Infrastructure funding.
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Glossary
- Bulk EVs
-
The entire vesicular population (including onco-extracellular vesicles and all other subtypes) present in biofluids, originating from multiple organs, tissues and cell types.
- Exosomes
-
A major class of extracellular vesicle (typically 30–150 nm in diameter) of endocytic origin released by all cell types following fusion of multivesicular bodies with the plasma membrane.
- Extracellular vesicles
-
(EVs). Lipid membrane-encapsulated particles released by cells into the intercellular space and/or circulation that enable bidirectional cell–cell communication. EVs comprise various subclasses based on their molecular cargo, biogenesis and biophysical properties.
- Liquid biopsy
-
Analysis of blood samples to identify circulating cancer biomarkers that can aid in clinical diagnosis and disease prognosis.
- Microparticles
-
A major class of membranous extracellular vesicles (typically, 50–1,500 nm in diameter) formed by direct budding from the plasma membrane; microparticles can also be known as microvesicles and ectosomes.
- Nanoparticles
-
Synthetic, lipid-based, polymeric and inorganic nanostructures (typically <100 nm in diameter) that determine their functionality, activity and utility for drug delivery applications.
- Nanoscopy
-
Use of light microscopy technique with diffraction-unlimited spatial resolution, which produces high-resolution images at the nanometre scale (also known as single-molecule localization microscopy or super-resolution microscopy).
- Nanotherapeutics
-
The use of nanotechnology to design and deliver drugs and devices to treat a wide range of diseases, improve drug delivery and reduce toxicity.
- Non-vesicular extracellular particles
-
(NVEPs). Non-extracellular vesicle particles include plasma lipoproteins, protein aggregates, supermeres, exomeres and even viruses.
- Onco-EVs
-
Cancer cell-derived extracellular vesicles (EVs) that contain oncogenic cargoes (such as EV surface proteins, antigens, intracellular proteins, lipids, metabolites, RNAs, DNA fragments and others) that might augment cancer progression.
- Pre-metastatic niche
-
A microenvironment induced by factors released from the primary tumour in a distant organ that supports metastatic cell seeding, survival and outgrowth. Such factors include tumour cell-derived exosomes and extracellular vesicles.
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Greening, D.W., Xu, R., Rai, A. et al. Clinical relevance of extracellular vesicles in cancer — therapeutic and diagnostic potential. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01074-2
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DOI: https://doi.org/10.1038/s41571-025-01074-2
