Pulmonary delivery of clofoctol-loaded nanoparticles inhibits SARS-CoV-2 replication and reduces pneumonia

Abstract

Despite the progress made through vaccination campaigns and the use of antivirals, the need for more effective therapeutics to combat respiratory viral infections remains critical. A recent screening of over 2000 repurposed molecules has identified the antibiotic clofoctol (CFT) as a promising candidate for treating COVID-19. However, administering CFT systemically poses challenges due to its low solubility and potential toxicity. In this study, we engineered poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) designed to encapsulate high payloads of CFT, allowing for a controlled drug release in the pulmonary environment. Pharmacokinetic studies demonstrated high CFT bioavailability 8 h after intranasal (i.n.) administration. In preclinical models (mouse and hamster) of COVID-19, i.n. administration of CFT-loaded NPs significantly reduced pulmonary viral loads. Remarkably, vectorized CFT also decreased inflammation and improved pathological scores in the lungs. These results pave the way for a groundbreaking CFT formulation designed to tackle the challenges posed by acute respiratory infections. This study marks the first demonstration of a stable, effective and well-tolerated CFT formulation for the treatment of lung diseases.

Keywords: COVID-19; Clofoctol; Lung infection; Lung inflammation; Nanomedicine; PLGA nanoparticles.