Bottlebrush polyethylene glycol nanocarriers translocate across human airway epithelium via molecular architecture enhanced endocytosis.
bioRxiv
; 2024 Feb 16.
Article
en En
| MEDLINE
| ID: mdl-38405944
ABSTRACT
Pulmonary drug delivery is critical to the treatment of respiratory diseases. However, the human airway surface presents multiscale barriers to efficient drug delivery. Here we report a bottlebrush polyethylene glycol (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface. Guided by the molecular theory, we design a PEG-BB molecule consisting of a linear backbone densely grafted by many (â¼1,000) low molecular weight (â¼1000 g/mol) PEG chains; this results in a highly anisotropic, wormlike nanocarrier featuring a contour length of â¼250 nm, a cross-section of â¼20 nm, and a hydrodynamic diameter of â¼40 nm. Using the classic air-liquid-interface culture system to recapitulate essential biological features of the human airway surface, we show that PEG-BB rapidly penetrates through endogenous airway mucus and periciliary brush layer (mesh size of 20-40 nm) to be internalized by cells across the whole epithelium. By quantifying the cellular uptake of polymeric carriers of various molecular architectures and manipulating cell proliferation and endocytosis pathways, we show that the translocation of PEG-BB across the epithelium is driven by bottlebrush architecture enhanced endocytosis. Our results demonstrate that large, wormlike bottlebrush PEG polymers, if properly designed, can be used as a novel carrier for pulmonary and mucosal drug delivery.
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MEDLINE
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En
Revista:
BioRxiv
Año:
2024
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Article