The mucus barrier is well established as a formidable barrier to exogenous substances and forms the first line of defense for mucosal surfaces. Drugs and particle systems are known to be significantly hindered via a variety of interactions with mucus, and some efforts have been reported that can mitigate these interactions. We investigated topically applied particulate systems (nano and micro) for their potential to interact with mucus and influence on the diffusion of model drugs across the mucus barrier. Functionalized polystyrene nanoparticles and microparticles and diesel particulate matter were topically applied to established in vitro mucus models. Particle treated mucus was then assessed, compared to controls, for drug permeation rates. The average permeation rate of drugs increased 2-fold following the application of particles to mucus compared to permeation of the same drug through mucus alone. In some cases permeation enhancement of small model drugs was over 5 times that of controls. Assessment of particle physicochemical properties also indicated that significant interactions occurred between mucus and the particles as determined by zeta potential changes and size changes. Collectively this work supports the hypothesis that topically applied particles interact with the mucus barrier causing disruption of this barrier allowing for increased drug permeation. These findings have implications for improved drug delivery and enhanced environmental exposure to exogenous substances.