Mucociliary clearance (MC), designed by evolution to eliminate inhaled and possibly noxious material from the airways, considerably limits the benefit of inhalation therapy. Although the principles of MC seem to be understood, there are still many open questions on mucociliary particle clearance. In this study a trachea-based in vitro model was used to investigate the effect of particle size, zeta-potential, and mucoadhesive particle properties on mucociliary particle clearance. As different sized particles (50-6000 nm) were tested at equal mass concentrations, size related factors, namely particle number and particle surface area, varied by several orders of magnitude between the experiments. Surprisingly, particle clearance for 50 nm up to 6000 nm-sized polystyrene particles did not differ significantly (p < 0.05): 50 nm (2.9 +/- 0.6 mm/min); 100 nm (3.8 +/- 0.9 mm/min); 1000 nm (3.8 +/- 0.8 mm/min); 6000 nm (3.2 +/- 0.6 mm/min). In clear contrast, particles prepared from different PLGA-based copolymers (polylactic-co-glycolic acid) showed a significant effect on particle transport. PEG-PLGA particles (polyethylene glycol) showed the fastest and normal transport rates (5.9 +/- 1.7 mm/min) compared to the ICRP's (International Commission of Radiological Protection) standard value for average tracheal transport rates (5.5 mm/min). Mucoadhesive chitosan-PLGA particles were transported at the slowest rate (0.7 +/- 0.3 mm/min) of all particles tested. Overall, particle size and zeta-potential seem to be relatively uncritical, whereas material properties and the related particle surface chemistry significantly influence mucociliary particle clearance. Considering these findings in future drug formulation seems to be a promising strategy to improve inhalation therapy by prolonged particle/drug residence time within the airways.