Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma
Open accessAbstract
MicroRNAs (miRNAs) circulate in the bloodstream in a highly stable, extracellular form and are being developed as blood-based biomarkers for cancer and other diseases. However, the mechanism underlying their remarkable stability in the RNase-rich environment of blood is not well understood. The current model in the literature posits that circulating miRNAs are protected by encapsulation in membrane-bound vesicles such as exosomes, but this has not been systematically studied. We used differential centrifugation and size-exclusion chromatography as orthogonal approaches to characterize circulating miRNA complexes in human plasma and serum. We found, surprisingly, that the majority of circulating miRNAs cofractionated with protein complexes rather than with vesicles. miRNAs were also sensitive to protease treatment of plasma, indicating that protein complexes protect circulating miRNAs from plasma RNases. Further characterization revealed that Argonaute2 (Ago2), the key effector protein of miRNA-mediated silencing, was present in human plasma and eluted with plasma miRNAs in size-exclusion chromatography. Furthermore, immunoprecipitation of Ago2 from plasma readily recovered non-vesicle-associated plasma miRNAs. The majority of miRNAs studied copurified with the Ago2 ribonucleoprotein complex, but a minority of specific miRNAs associated predominantly with vesicles. Our results reveal two populations of circulating miRNAs and suggest that circulating Ago2 complexes are a mechanism responsible for the stability of plasma miRNAs. Our study has important implications for the development of biomarker approaches based on capture and analysis of circulating miRNAs. In addition, identification of extracellular Ago2-miRNA complexes in plasma raises the possibility that cells release a functional miRNA-induced silencing complex into the circulation.
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Many studies have detected extracellular/circulating miRNAs in biological fluids such as plasma, serum, cerebrospinal fluid, saliva, breast milk, urine, tears, colostrum, peritoneal fluid, bronchial lavage, seminal fluid, and ovarian follicular fluid.
“Many studies have detected extracellular/circulating miRNAs in biological fluids, such as plasma and serum (117, 118), cerebrospinal fluid (119), saliva (120), breast milk (121), urine, tears, colostrum, peritoneal fluid, bronchial lavage, seminal fluid (122), and ovarian follicular fluid (123).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [118]
MiRNAs are relatively stable in CSF, plasma, and EVs, in part because they are protected within vesicles or Argonaute-containing protein complexes.
“MiRNAs are relatively stable in CSF, plasma, and EVs, in part because they are protected within vesicles or Argonaute-containing protein complexes, making them attractive candidates for minimally invasive biomarkers and disease-staging tools in AD (Arroyo et al., 2011; Siedlecki-Wullich et al., 2021).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Arroyo et al., 2011
Prior reports have found miRNAs to be relatively stable in various biological media, including blood and stool.
“Prior reports have found miRNAs to be relatively stable in various biological media, including blood and stool [16, 17].”
From Novel Approach to Fecal Occult Blood Testing by Assay of Erythrocyte-Specific microRNA Markers (2017) · cites this paper as [16]
An additional 12 control arrays were performed on serial 2-fold dilutions of 30 μl of plasma from a single healthy donor to determine the analytic measurement ranges for each qPCR assay on the Exiqon array.
“An additional 12 control arrays were performed on serial 2-fold dilutions of 30 μl of plasma from a single healthy donor to determine the analytic measurement ranges for each qPCR assay on the Exiqon array as previously described (7).”
From Blood Cell Origin of Circulating MicroRNAs: A Cautionary Note for Cancer Biomarker Studies (2012) · cites this paper as [7]
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Brindley, E., Heiland, M., Mooney, C., Diviney, M., Mamad, O., Hill, T. D. M., Yan, Y., Venø, M. T., Reschke, C. R., Batool, A., et al. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1230942 · Cited by 21 · see citing works
Old problem, new solutions: biomarker discovery for acetaminophen liver toxicity
Gloor, Y., Schvartz, D., & F.Samer, C. (2019) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2019.1642323 · Cited by 18 · see citing works
Shanthi, K., Fischer, D., Sharma, A., Kiviniemi, A., Kaakinen, M., Vainio, S., & Bart, G. (2023) · Genes · doi:10.3390/genes14040853 · Cited by 5 · see citing works
Alzheim(i)R: MicroRNAs in Alzheimer’s Disease
Barbato, C. (2014) · Journal of Cytology & Histology · doi:10.4172/2157-7099.1000e113 · Cited by 3 · see citing works
Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease
Donepudi, K., Eadha, S., Rodarte, D., Sharma, B., & Kumar, S. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103211
- Authors
- Arroyo, J. D., Chevillet, J. R., Kroh, E. M., Ruf, I. K., Pritchard, C. C., Gibson, D. F., Mitchell, P. S., Bennett, C. F., Pogosova-Agadjanyan, E. L., Stirewalt, D. L., Tait, J. F., & Tewari, M.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington Medical Center (US)
- University of Washington (US)
- Divisions of dClinical Research and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-03-07
- Volume
- 108
- Issue
- 12
- Pages
- 5003-5008
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3064324
- OpenAlex
- W2024206172
- Cited by
- 3,294
- References
- 31
- Citations by year
- 2026: 119 · 2025: 129 · 2024: 134 · 2023: 175 · 2022: 177 · 2021: 280 · 2020: 274 · 2019: 265 · 2018: 265 · 2017: 243 · 2016: 260 · 2015: 288 · 2014: 247 · 2013: 244 · 2012: 139
- FWCI
- 73.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 085714, R01DK085714)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- circulating microRNAs, Argonaute 2, extracellular vesicles, exosomes, RNase resistance, protein complexes, miRNA-induced silencing complex, blood-based biomarkers
- MeSH terms
- Humans, Plasma, Ribonucleoproteins, Eukaryotic Initiation Factor-2, MicroRNAs, Cell-Derived Microparticles, Argonaute Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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