Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles.
Nat Biomed Eng
; 5(9): 1084-1098, 2021 09.
Article
in En
| MEDLINE
| ID: mdl-34616047
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Extracellular Vesicles
/
Neuroinflammatory Diseases
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Nat Biomed Eng
Year:
2021
Document type:
Article
Affiliation country:
Sweden
Publication country:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM