Airway epithelial-targeted nanoparticle reverses asthma in inhalation therapy.

Despite extensive research on corticosteroids for treating asthma, their short residence time in the lungs has limited their therapeutic effects in vivo. Nanoparticles have been widely investigated for inhaled drug delivery due to their potential benefits in prolonging drugs' residence time in the lungs. However, the retention of nanoparticles may be limited by mucus and ciliated epithelium clearance mechanisms in the airway. Herein, we anchored a neonatal-Fc-receptor-targeted peptide (FcBP) onto "mucus-penetrating" polyethylene glycol (PEG) nanoparticles (PEG-NP). Interestingly, the mucus-permeability of PEG-NP was not impaired by FcBP-functionalization. Moreover, FcBP modification enhanced cellular internalization and exocytosis via specific receptor-mediated processes, which subsequently ameliorated transepithelial transport and prolonged pulmonary retention. Importantly, after loading dexamethasone, FcBP-functionalization could effectively help nanoparticles cross the airway epithelial layer and be endocytosed by inflammatory cells, resulting in a marked decrease in inflammatory cytokines. Finally, FcBP modification significantly enhanced the therapeutic effect of dexamethasone-loaded nanoparticles in asthma mice. This study demonstrates that FcBP-functionalized PEG-NP can overcome multiple obstacles in the airway to prolong the pulmonary retention of drugs, providing a promising strategy for inhalation therapy.