Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
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...
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| Veröffentlicht in: | NATURE BIOMEDICAL ENGINEERING 2021-09, Vol.5 (9), p.1084-1098 |
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| creator | Gupta, Dhanu Wiklander, Oscar P. B. Görgens, André Conceição, Mariana Corso, Giulia Liang, Xiuming Seow, Yiqi Balusu, Sriram Feldin, Ulrika Bostancioglu, Beklem Jawad, Rim Mamand, Doste R. Lee, Yi Xin Fiona Hean, Justin Mäger, Imre Roberts, Thomas C. Gustafsson, Manuela Mohammad, Dara K. Sork, Helena Backlund, Alexandra Lundin, Per de Fougerolles, Antonin Smith, C. I. Edvard Wood, Matthew J. A. Vandenbroucke, Roosmarijn E. Nordin, Joel Z. El-Andaloussi, Samir |
| description | 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-α) 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-α and IL-6 pathways.
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. |
| doi_str_mv | 10.1038/s41551-021-00792-z |
| format | Article |
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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-α) 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-α and IL-6 pathways.
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B.</au><au>Görgens, André</au><au>Conceição, Mariana</au><au>Corso, Giulia</au><au>Liang, Xiuming</au><au>Seow, Yiqi</au><au>Balusu, Sriram</au><au>Feldin, Ulrika</au><au>Bostancioglu, Beklem</au><au>Jawad, Rim</au><au>Mamand, Doste R.</au><au>Lee, Yi Xin Fiona</au><au>Hean, Justin</au><au>Mäger, Imre</au><au>Roberts, Thomas C.</au><au>Gustafsson, Manuela</au><au>Mohammad, Dara K.</au><au>Sork, Helena</au><au>Backlund, Alexandra</au><au>Lundin, Per</au><au>de Fougerolles, Antonin</au><au>Smith, C. I. Edvard</au><au>Wood, Matthew J. A.</au><au>Vandenbroucke, Roosmarijn E.</au><au>Nordin, Joel Z.</au><au>El-Andaloussi, Samir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles</atitle><jtitle>NATURE BIOMEDICAL ENGINEERING</jtitle><stitle>Nat Biomed Eng</stitle><addtitle>Nat Biomed Eng</addtitle><date>2021-09-01</date><risdate>2021</risdate><volume>5</volume><issue>9</issue><spage>1084</spage><epage>1098</epage><pages>1084-1098</pages><issn>2157-846X</issn><eissn>2157-846X</eissn><abstract>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-α) 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-α and IL-6 pathways.
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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34616047</pmid><doi>10.1038/s41551-021-00792-z</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-0163-2678</orcidid><orcidid>https://orcid.org/0000-0001-9198-0857</orcidid><orcidid>https://orcid.org/0000-0002-3653-7710</orcidid><orcidid>https://orcid.org/0000-0001-6755-6968</orcidid><orcidid>https://orcid.org/0000-0003-4468-9113</orcidid><orcidid>https://orcid.org/0000-0003-2242-7227</orcidid><orcidid>https://orcid.org/0000-0002-3313-7631</orcidid><orcidid>https://orcid.org/0000-0003-1176-8114</orcidid><orcidid>https://orcid.org/0000-0002-1145-0862</orcidid><orcidid>https://orcid.org/0000-0003-1907-3392</orcidid><orcidid>https://orcid.org/0000-0002-8327-620X</orcidid><orcidid>https://orcid.org/0000-0002-9092-1932</orcidid><orcidid>https://orcid.org/0000-0002-5436-6011</orcidid><orcidid>https://orcid.org/0000-0001-9201-0991</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2157-846X |
| ispartof | NATURE BIOMEDICAL ENGINEERING, 2021-09, Vol.5 (9), p.1084-1098 |
| issn | 2157-846X 2157-846X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2580026481 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | 13/109 13/21 13/31 13/95 14 14/28 14/34 14/5 38/39 38/90 42/44 59/5 631/61 631/61/350/354 64/60 Adaptor proteins Animal models Animals Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biopharmaceuticals Cytokines Decoys Display devices Extracellular Vesicles Genetic engineering Inflammation Interleukin 6 Mice Neuroinflammatory Diseases Oligomerization Phenotypes Proteins Receptors Syndecan Tumor necrosis factor receptors Tumor Necrosis Factor-alpha Tumor necrosis factor-TNF Tumor necrosis factor-α Tumors Vesicles |
| title | Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles |
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