In a study directed towards non-invasive delivery of therapeutic biomacromolecules, we examined whether surface modification of sub-200 nm model nanoparticles with the Fc portion of IgG promotes their cell uptake and transport across the airway epithelial cells. The study initially confirms the expression of the relevant receptor, namely neonatal Fc receptor (FcRn), by Calu-3 cell layers simulating the airway epithelium and demonstrates FcRn-mediated cell association, internalization and transcellular transport of molecular IgG. Surface decoration of nanoparticles with the Fc portion of IgG enhanced both cell uptake and translocation of the particulate system across the cell layers, in a manner strongly suggesting FcRn involvement in these processes. The study further demonstrates the potential of Fc-modified nanoparticles to 'shuttle' a model therapeutic antibody fragment across the epithelial cell layers. Fc-modified nanoparticles are transported in the μg/h/cm(2) range, presenting a substantial increase in transport capacity in comparison to molecular IgG (ng/h/cm(2) range), therefore warranting consideration of the FcRn transcytotic pathway for further investigation as a means to achieve transmucosal delivery of nanoparticulate systems that could act as carriers of a range of biotherapeutics.