Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
| Autor: | Yiqi Seow, Beklem Bostancioglu, Matthew J.A. Wood, Mariana Conceição, Antonin de Fougerolles, Justin Hean, Samir El-Andaloussi, Imre Mäger, Doste R Mamand, Manuela O. Gustafsson, Oscar P. B. Wiklander, Per Lundin, Sriram Balusu, Helena Sork, Dhanu Gupta, Joel Z. Nordin, Alexandra Bäcklund, Yi Xin Fiona Lee, André Görgens, Dara K. Mohammad, C. I. Edvard Smith, Rim Jawad, Thomas C. Roberts, Giulia Corso, Ulrika Feldin, Xiuming Liang, Roosmarijn E. Vandenbroucke |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_treatment
Population Medizin Biomedical Engineering Medicine (miscellaneous) Bioengineering Systemic inflammation Syndecan 1 Extracellular Vesicles Mice medicine Animals Decoy receptors education Receptor Inflammation education.field_of_study Tumor Necrosis Factor-alpha Chemistry Computer Science Applications Cell biology Transmembrane domain Cytokine Neuroinflammatory Diseases Cytokines medicine.symptom Decoy Biotechnology |
| Zdroj: | Nature biomedical engineering |
| ISSN: | 2157-846X |
| DOI: | 10.1038/s41551-021-00792-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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