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Therapeutic delivery of drug and gene delivery systems have to traverse multiple biological barriers to achieve efficacy. Mucosal administration, such as pulmonary delivery in cystic fibrosis (CF) disease, remains a significant challenge due to concentrated viscoelastic mucus, which prevents drugs and particles from penetrating the mucus barrier. To address this problem, we used combinatorial peptide-presenting phage libraries and next-generation sequencing (NGS) to identify hydrophilic, net-neutral charged peptide coatings that enable penetration through human CF mucus ex vivo with ~600-fold better penetration than control, improve uptake into lung epithelial cells compared to uncoated or PEGylated-nanoparticles, and exhibit enhanced uniform distribution and retention in the mouse lung airways. These peptide coatings address multiple delivery barriers and effectively serve as excellent alternatives to …