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Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles

Dhanu Gupta, Oscar P. B. Wiklander, Andre Goergens, Mariana Conceicao, Giulia Corso, Xiuming Liang, Yiqi Seow, Sriram Balusu (UGent) , Ulrika Feldin, Beklem Bostancioglu, et al.
(2021) NATURE BIOMEDICAL ENGINEERING. 5(9). p.1084-1098
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Abstract
The loading of two different protein therapeutics onto extracellular vesicles can be optimized by genetically engineering the parent cells, as shown for extracellular vesicles displaying decoy receptors for two pro-inflammatory cytokines. Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-alpha and IL-6 pathways.
Keywords
DELIVERY, SIRNA, TNF, INTERLEUKIN-6

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MLA
Gupta, Dhanu, et al. “Amelioration of Systemic Inflammation via the Display of Two Different Decoy Protein Receptors on Extracellular Vesicles.” NATURE BIOMEDICAL ENGINEERING, vol. 5, no. 9, 2021, pp. 1084–98, doi:10.1038/s41551-021-00792-z.
APA
Gupta, D., Wiklander, O. P. B., Goergens, A., Conceicao, M., Corso, G., Liang, X., … El-Andaloussi, S. (2021). Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles. NATURE BIOMEDICAL ENGINEERING, 5(9), 1084–1098. https://doi.org/10.1038/s41551-021-00792-z
Chicago author-date
Gupta, Dhanu, Oscar P. B. Wiklander, Andre Goergens, Mariana Conceicao, Giulia Corso, Xiuming Liang, Yiqi Seow, et al. 2021. “Amelioration of Systemic Inflammation via the Display of Two Different Decoy Protein Receptors on Extracellular Vesicles.” NATURE BIOMEDICAL ENGINEERING 5 (9): 1084–98. https://doi.org/10.1038/s41551-021-00792-z.
Chicago author-date (all authors)
Gupta, Dhanu, Oscar P. B. Wiklander, Andre Goergens, Mariana Conceicao, Giulia Corso, Xiuming Liang, Yiqi Seow, Sriram Balusu, Ulrika Feldin, Beklem Bostancioglu, Rim Jawad, Doste R. Mamand, Yi Xin Fiona Lee, Justin Hean, Imre Mager, Thomas C. Roberts, Manuela Gustafsson, Dara K. Mohammad, Helena Sork, Alexandra Backlund, Per Lundin, Antonin de Fougerolles, C. I. Edvard Smith, Matthew J. A. Wood, Roosmarijn Vandenbroucke, Joel Z. Nordin, and Samir El-Andaloussi. 2021. “Amelioration of Systemic Inflammation via the Display of Two Different Decoy Protein Receptors on Extracellular Vesicles.” NATURE BIOMEDICAL ENGINEERING 5 (9): 1084–1098. doi:10.1038/s41551-021-00792-z.
Vancouver
1.
Gupta D, Wiklander OPB, Goergens A, Conceicao M, Corso G, Liang X, et al. Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles. NATURE BIOMEDICAL ENGINEERING. 2021;5(9):1084–98.
IEEE
[1]
D. Gupta et al., “Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles,” NATURE BIOMEDICAL ENGINEERING, vol. 5, no. 9, pp. 1084–1098, 2021.
@article{8728701,
  abstract     = {{The loading of two different protein therapeutics onto extracellular vesicles can be optimized by genetically engineering the parent cells, as shown for extracellular vesicles displaying decoy receptors for two pro-inflammatory cytokines. Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-alpha and IL-6 pathways.}},
  author       = {{Gupta, Dhanu and Wiklander, Oscar P. B. and Goergens, Andre and Conceicao, Mariana and Corso, Giulia and Liang, Xiuming and Seow, Yiqi and Balusu, Sriram and Feldin, Ulrika and Bostancioglu, Beklem and Jawad, Rim and Mamand, Doste R. and Lee, Yi Xin Fiona and Hean, Justin and Mager, Imre and Roberts, Thomas C. and Gustafsson, Manuela and Mohammad, Dara K. and Sork, Helena and Backlund, Alexandra and Lundin, Per and de Fougerolles, Antonin and Smith, C. I. Edvard and Wood, Matthew J. A. and Vandenbroucke, Roosmarijn and Nordin, Joel Z. and El-Andaloussi, Samir}},
  issn         = {{2157-846X}},
  journal      = {{NATURE BIOMEDICAL ENGINEERING}},
  keywords     = {{DELIVERY,SIRNA,TNF,INTERLEUKIN-6}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1084--1098}},
  title        = {{Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles}},
  url          = {{http://doi.org/10.1038/s41551-021-00792-z}},
  volume       = {{5}},
  year         = {{2021}},
}
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