Peptides As Surface Coatings of Nanoparticles That Penetrate Human Cystic Fibrosis Sputum and Uniformly Distribute In Vivo Following Pulmonary Delivery

In mucosal-associated diseases, drug and gene delivery systems have to traverse multiple biological barriers to achieve therapeutic efficacy. In particular, in select pulmonary diseases such as cystic fibrosis (CF), therapeutic delivery remains a significant challenge due to concentrated viscoelastic mucus, which prevents effective penetration and transmucosal transport of drugs and particles. To address this problem, we used combinatorial peptide-presenting phage libraries with next-generation DNA sequencing to identify hydrophilic, net-neutral charged peptides as coatings that enable penetration of human CF mucus ex vivo with ~600-fold better penetration than control. In addition, these peptide coatings improve uptake into lung epithelial cells compared to uncoated or standard poly(ethylene glycol) (PEG)-functionalized 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 standard PEG surface chemistries to achieve mucus penetration and address some of the challenges encountered using these chemistries. This biomolecule-based strategy can address multiple delivery barriers and hold promise to advance efficacy of therapeutics for diseases like CF.