Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
Author: 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
Department: Inst för laboratoriemedicin / Dept of Laboratory Medicine
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Author Accepted Manuscript (4.022Mb)
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.
Institution:
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Department of Paediatrics, University of Oxford, Oxford, UK
- Molecular Engineering Laboratory, Institute for Bioengineering and Nanotechnology, A*STAR, Singapore, Singapore
- VIB Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Biology Department, Cihan University-Erbil, Erbil, Iraq
- Genome Institute of Singapore, Agency for Science, Technology and Research, A*STAR, Singapore, Singapore
- Evox Therapeutics Limited, Oxford, UK
- MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK
- College of Agricultural Engineering Sciences, Salahaddin University-Erbil, Erbil, Iraq
- Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institute, Stockholm, Sweden
Citation: Nat Biomed Eng. 2021 Sep;5(9):1084-1098.
Citation DOI: 10.1038/s41551-021-00792-z
Citation PMID: 34616047
Citation ISI: 000704434100005
Publishing journal: Nature Biomedical Engineering
Eprint status: Peer Reviewed
Version: Accepted
Issue date: 2022-12-06
Sponsorship:
- International Society for Advancement of Cytometry Marylou Ingram Scholar 2019-2023
- H2020 EXPERT
- Swedish foundation of Strategic Research (SSF-IRC; FormulaEx)
- ERC CoG (DELIVER)
- Swedish Medical Research Council
Rights:
Article is made available in accordance with the publisher's policy and may be subject to copyright law. Please refer to the publisher's site for terms of use.
Publication year: 2021
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