Mucus is a complex hydrogel that acts as a protective barrier in various parts of the human body. Both composition and structural properties play a crucial role in maintaining barrier properties while dictating diffusion of molecules and (nano)­materials. In this study, we compare previously described mucus surrogates with the native human airway and pig intestinal mucus. Oscillatory shear rheology was applied to characterize mucus on the bulk macrorheological level, revealing that the artificial airway surrogate deviates from the elastic-dominant behavior of native mucus samples. We circumvented this limitation through the addition of a cross-linking polymer to the surrogate, adjusting the rheological properties closer to those of native mucus. Applying particle tracking microrheology, we further demonstrated that the mechanical properties at the microscale differ significantly between artificial and native mucus. We conclude that proper characterization of mucus and its surrogates is vital for a reliable investigation of nanoparticle-based mucosal drug delivery.

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