Combined Effect of Size and Charge on the Interaction of Na-noparticles with Mucus-Mimicking Mucin Hydrogels

Background/Objectives: Understanding the interactions between nanoparticles and mucosal tissues is crucial for the development of advanced drug delivery systems, as the diffusion behavior of nanoparticles through mucus is strongly influenced by their size and surface properties, and the viscoelastic nature of the hydrogel matrix. In this study, we investigated the impact of nanoparticle size, surface charge, and hydrogel crosslinking density on nanoparticle diffusion in mucus. Method: Citrate-stabilized and PEGylated 30- and 100-nm gold nanoparticles were used as a model of nanopar-ticle and their diffusion through mucus-mimicking mucin-based hydrogels of two different crosslinking densities was assessed. Results: Citrate-stabilized 30-nm nano-particles demonstrated greater diffusion in hydrogels mimicking native mucus com-pared to more densely crosslinked ones. This size-dependent effect was not observed for the 100-nm citrate-stabilized nanoparticles, which showed limited diffusion in both hydrogel types. To confer different surface-charge, gold nanoparticles were function-alized by the conjugation of poly(ethylene glycol) (PEG) derivatives of identical mo-lecular weight though bearing different terminal moieties (neutral, and positively- and negatively charged) to modulate the surface charge and assess their interaction with the negatively-charge mucin matrix. PEGylated nanoparticles exhibited significantly greater mobility than their citrate-stabilized counterparts, regardless of size or hydro-gel density. Among PEGylated particles, the neutral and negatively charged 30-nm variants demonstrated higher diffusion than the positively charged ones. For the 100-nm particles, the neutral PEGylated nanoparticles diffused more than the posi-tively charged counterparts. Conclusions: These findings could provide valuable in-sights into the more rational design of nanoparticle-based drug delivery systems tar-geting mucosal tissues.