Nature biomedical engineering · 2021
Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.