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Loss of functional cystic fibrosis transmembrane receptor (CFTR) leads to acidification and oxidation of airway surface mucus. Replacing bicarbonate (HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>) topically fails due to rapid reabsorption and neutralization, while the scavenging antioxidant, glutathione sulfhydryl (GSH), is also rapidly degraded. The objective of this study is to investigate GSH\/NaHCO<jats:sub>3<\/jats:sub> nanoparticles as novel strategy for CF airway disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>GSH\/NaHCO<jats:sub>3<\/jats:sub> poly (lactic\u2010co\u2010glycolic acid) nanoparticles were tested on primary CF (F508del\/F508del) epithelial cultures to evaluate dose\u2010release curves, surface pH, toxicity, and MCT indices using micro\u2010optical coherence tomography. In vivo tests were performed in three rabbits to assess safety and toxicity. After 1\u00a0week of daily injections, histopathology, computed tomography (CT), and blood chemistries were performed and compared to three controls. Fluorescent nanoparticles were injected into a rabbit with maxillary sinusitis and explants visualized with confocal microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sustained release of GSH and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> with no cellular toxicity was observed over 2\u00a0weeks. Apical surface pH gradually increased from 6.54\u00a0\u00b1\u00a00.13 (baseline) to 7.07\u00a0\u00b1\u00a00.10 (24\u00a0h) (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001) and 6.87 \u00b1 0.05 at 14 days (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001). MCT, ciliary beat frequency, and periciliary liquid were significantly increased. When injected into the maxillary sinuses of rabbits, there were no changes to histology, CT, or blood chemistries. Nanoparticles penetrated rabbit sinusitis mucus on confocal microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Findings suggest that GSH\/NaHCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> nanoparticles are a promising treatment option for viscous mucus in CF and other respiratory diseases of mucus obstruction such as chronic rhinosinusitis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/alr.23301","type":"journal-article","created":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T03:47:23Z","timestamp":1700279243000},"page":"1026-1035","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Glutathione and bicarbonate nanoparticles improve mucociliary transport in cystic fibrosis epithelia"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5173-8959","authenticated-orcid":false,"given":"Do 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