Efficient production and enhanced tumor delivery of engineered extracellular vesicles
Open accessAbstract
Extracellular vesicles (EV), including exosomes and microvesicles, are nano-sized intercellular communication vehicles that participate in a multitude of physiological processes. Due to their biological properties, they are also promising candidates for the systemic delivery of therapeutic compounds, such as cytokines, chemotherapeutic drugs, siRNAs and viral vectors. However, low EV production yield and rapid clearance of administered EV by liver macrophages limit their potential use as therapeutic vehicles. We have used a hollow-fiber bioreactor for the efficient production of bioactive EV bearing the heterodimeric cytokine complex Interleukin-15:Interleukin-15 receptor alpha. Bioreactor culture yielded ∼40-fold more EV per mL conditioned medium, as compared to conventional cell culture. Biophysical analysis and comparative proteomics suggested a more diverse population of EV in the bioreactor preparations, while serum protein contaminants were detectable only in conventional culture EV preparations. We also identified the Scavenger Receptor Class A family (SR-A) as a novel monocyte/macrophage uptake receptor for EV. In vivo blockade of SR-A with dextran sulfate dramatically decreased EV liver clearance in mice, while enhancing tumor accumulation. These findings facilitate development of EV therapeutic methods.
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Watson et al. showed that yield of exosomes can be increased by 5-10 fold using a hollow fiber bioreactor.
“Watson et al. (38) showed that yield of exosomes can be increased by 5–10 fold using a hollow fiber bioreactor.”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [38]
Results §3.1 reports approximately fivefold more extracellular vesicles (EV) from bioreactor-conditioned medium than from conventional flasks. The tenfold total improvement also required an optimized purification step. The paper measures EV, a category that includes exosomes, rather than establishing a five- to tenfold increase specifically in exosome yield from the bioreactor alone. (LLM, conf=0.88)
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- Authors
- Watson, D. C., Bayik, D., Srivatsan, A., Bergamaschi, C., Valentin, A., Niu, G., Bear, J., Monninger, M., Sun, M., Morales-Kastresana, A., Jones, J. C., Felber, B. K., Chen, X., Gursel, I., & Pavlakis, G. N.
- Affiliations
- University of Patras (GR)
- National Institutes of Health (US)
- National Cancer Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- United States Army Medical Research Institute of Infectious Diseases (US)
- Corresponding author
- Pavlakis, George N.
- ORCID
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 105
- Pages
- 195-205
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC7156278
- OpenAlex
- W2466551530
- Cited by
- 385
- References
- 40
- Citations by year
- 2026: 25 · 2025: 45 · 2024: 44 · 2023: 41 · 2022: 62 · 2021: 45 · 2020: 55 · 2019: 30 · 2018: 22 · 2017: 15 · 2016: 1
- FWCI
- 11.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biomaterials (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Bilkent University Institutional Repository (Bilkent University) (submittedVersion)
- Funders
- Intramural Research Program of the National Institutes of Health
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- extracellular vesicles, exosomes, hollow fiber bioreactor, IL-15, IL-15Rα, cytokine delivery, tumor accumulation, hepatic clearance, scavenger receptor A, dextran sulfate, EV proteomics
- MeSH terms
- Extracellular Vesicles, Cell Fractionation, Cells, Cultured, Equipment Design, Humans, Macrophages, Neoplasms, Experimental, Bioreactors, Tissue Engineering, HEK293 Cells, Batch Cell Culture Techniques
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