Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Dec;22(1):1-7.
doi: 10.1080/15476286.2024.2446868. Epub 2024 Dec 24.

Relevance of RNA to the therapeutic efficacy of mesenchymal stromal/stem cells extracellular vesicles

Thong Teck Tan  1 , Sai Kiang Lim  1   2
Affiliations
Review

Relevance of RNA to the therapeutic efficacy of mesenchymal stromal/stem cells extracellular vesicles

Thong Teck Tan et al. RNA Biol. 2025 Dec.

Erratum in

  • Correction.
    [No authors listed] [No authors listed] RNA Biol. 2025 Dec;22(1):1. doi: 10.1080/15476286.2025.2449742. Epub 2025 Jan 7. RNA Biol. 2025. PMID: 39773269 No abstract available.

Abstract

Mesenchymal Stromal/Stem Cells (MSCs) are among the most frequently studied cell types in clinical trials, and their small extracellular vesicles (sEVs) are now being extensively investigated for therapeutic applications. The RNA cargo of MSC-sEVs, particularly miRNAs and mRNAs, is widely believed to be a key therapeutic component of these vesicles. In this review, we critically examine using first principles and peer-reviewed literature, whether MSC- extracellular vesicles (MSC-EVs) can deliver sufficient quantity of functional miRNA or mRNA to target compartments within recipient cells to elicit a pharmacological response. Several RNA sequencing studies reveal that miRNAs are underrepresented in the small RNA population of MSC-sEVs compared to the parent MSCs. Additionally, the majority of miRNAs are mature forms that are not associated with Argonaute (AGO) proteins, essential for their function in RNA-induced silencing complexes (RISCs). Compounding this, cellular uptake of EVs is generally inefficient, with less than 1% being internalized, and only a fraction of these reaching the cytosol. This suggests that EVs may not deliver miRNAs in sufficient quantities to meaningfully interact with AGO proteins, either through canonical or non-canonical pathways, or with other proteins like Toll-like receptors (TLRs). Further, MSC-sEV RNAs are generally small, with sizes less than 500 nucleotides indicating that any mRNA present is likely fragmented as the average mammalian mRNA is approximately 2000 nucleotides, a fact confirmed by RNA sequencing data. Together, these findings challenge the notion that RNA, particularly miRNAs and mRNAs, are primary therapeutic attributes of MSC-sEVs.

Keywords: Extracellular vesicles (EVs); Mechanism of action; Mesenchymal Stem/Stromal Cell (MSC); MicroRNA (miRNA); RNA.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1a.
Figure 1a.
EV publications on therapy and diagnostics.
Figure 1b.
Figure 1b.
Publications on EVs and types of RNA.
Figure 1c.
Figure 1c.
Publications on EVs and RNA for therapy and diagnostics.
Figure 1d.
Figure 1d.
Cell source of EV RNA for therapy.
Figure 1e.
Figure 1e.
The limitations of an RNA-based hypothesis for MSC-EV therapeutic activity.
See this image and copyright information in PMC

References

    1. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy. 2006;8(4):315–317. doi: 10.1080/14653240600855905 - DOI - PubMed
    1. Ghannam S, Bouffi C, Djouad F, et al. Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. STEM Cell Res Ther. 2010;1(1):2. doi: 10.1186/scrt2 - DOI - PMC - PubMed
    1. Timmers L, Lim SK, Arslan F, et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res. 2008;1(2):129–137. - PubMed
    1. Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4(3):214–222. doi: 10.1016/j.scr.2009.12.003 - DOI - PubMed
    1. Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20(5):1053–1067. doi: 10.1681/ASN.2008070798 - DOI - PMC - PubMed

MeSH terms

LinkOut - more resources