Here, the preparation of mucus-penetrating nanoparticles for pulmonary administration of ibuprofen in patients with cystic fibrosis is described. A fluorescent derivative of alpha,beta-poly(N-2-hydroxyethyl)-D,L-aspartamide is synthesized by derivatization with rhodamine, polylactide, and poly(ethylene glycol), to obtain polyaspartamide-polylactide derivatives with different degrees of pegylation. Starting from these copolythers, fluorescent nanoparticles with different poly(ethylene glycol) content, empty and loaded with ibuprofen, showed spherical shape, colloidal size; slightly negative zeta potential, and biocompatibility toward human bronchial epithelial cells. The high surface poly(ethylene glycol) density of fluorescent nanoparticles and poly(ethylene glycol) brush-like conformation assumed on their surface, confefred to pegylated nanoparticles the mucus-penetrating properties, properly demonstrated by assessing their ability to avoid interactions with mucus components and to penetrate cystic fibrosis artificial mucus. Finally, ibuprofen release profile and uptake capacity-within human bronchial epithelial cells in the presence of cystic fibrosis artificial mucus showed how these mucus-penetrating nanoparticles timid rapidly diffuse through the mucus barrier reaching the mucosal surface, where they could offer a sustained delivery of ibuprofen at the site of disease