Nanonization of poorly water-soluble drugs has shown great potential in improving their oral bioavailability by enhancing the dissolution rate and saturation solubility. Moreover, due to particle size reduction and larger surface area, the number of contact points with the gastrointestinal mucus favors adhesion. Similar phenomena could be anticipated when nano-pollutants come into direct contact with mucosal tissues. However, the fundamental features that govern the interaction of particles with mucus have not been investigated in a systematic and rational way before. In this work, we synthesize mucin hydrogels of different pore sizes with rheological properties that closely mimic the properties of freshly extracted porcine mucin. By using fluorescent pure curcumin particles, we characterize the effect of particle size (hydrodynamic diameter of 200 nm, and 1.2 and 1.3 μm), concentration (18, 35, and 71 μg mL−1), and hydrogel crosslinking density (which is directly related to the stiffness and governs the average pore size) on the diffusion-driven particle penetration in vitro. Next, we derive a phenomenological model that describes the physics behind the diffusion-derived penetration of particles into the mucin network and considers the contributions of the particle size, the particle concentration, and the crosslinking density of the mucin hydrogel. Finally, we challenge our experimental-theoretical approach by preliminarily assessing the oral pharmacokinetics of an anti-cancer model drug, namely dasatinib, in pristine and nanonized forms and two clinically relevant doses in rats. For of a dose of 10 mg kg−1, drug nanonization leads to a significant ~8- and ~21-fold increase of the drug oral bioavailability and half-life, respectively, with respect to the unprocessed micron-sized drug. When the drug dose of pure drug nanoparticles (which is directly related to the local concentration of the drug in the gastrointestinal tract) was increased to 15 mg mL−1, the oral bioavailability increased though not significantly, suggesting the saturation of the penetration sites in the mucus, as demonstrated by the in vitro model. Our overall results reveal the potential of this experimental-theoretical approach, shed light on the interaction of particulate matter and mucosal tissues, and pave the way for the development of tools that enable a more rational design of nano-drug delivery systems for mucosal administration and the assessment of risk factors related to the exposure of mucosal tissues to nano-pollutants.

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