Brownian dynamics simulation of nanoparticle diffusion in mucus

Nanoparticles hold great promise as carriers for delivering drugs and genetic material to the lungs. However, their effectiveness is severely limited by the protective mucus barrier, which is highly viscoelastic and adhesive. This challenge is particularly pronounced in cystic fibrosis, where the mucus is more concentrated. Despite extensive efforts, the mechanisms governing nanoparticle transport in mucus remain poorly understood, limiting the rational design of delivery systems. This dissertation employs Brownian dynamics simulations to investigate the diffusion of spherical and rod-shaped nanoparticles in polymeric gels mimicking airway mucus. The models combine excluded volume effects, electrostatic interactions, and adhesive binding to capture the complex microenvironment. Three main studies are presented. First, spherical lipid nanoparticles are examined in gels modeled by a regular and periodic lattice formed by polymer chains. The simulations quantify how factors such as mucin concentration, surface charge, pH, and surface modification (PEGylation) influence nanoparticle mobility. The results clarify why neutral, hydrophilic coatings improve penetration and why cystic fibrosis-like mucus severely restricts transport. Second, the diffusion of rod-like nanoparticles is investigated in disordered gels. The role of particle aspect ratio is systematically evaluated under both steric and adhesive interactions. The findings reveal that elongated particles can exhibit greater mobility than previously anticipated by an obstruction-scaling model. Our model further reveals a competition between steric and adhesive interactions. Steric repulsion restricts access to adhesion sites and yields diffusivities intermediate between the purely steric and purely adhesive limits. Finally, the impact of shear flow on gel structure and nanosphere transport is investigated. We demonstrate how the shear flow aligns the mucin fibers predominantly streamwise. Accordingly, the nanosphere transport exhibits anisotropy, with the diffusivity much enhanced in the flow direction and suppressed in the two transverse directions. This work paves the way toward studying more clinically relevant scenarios, such as mucociliary clearance. Together, these studies provide a comprehensive framework for understanding nanoparticle transport through healthy and diseased mucus. The results bridge experimental findings and theoretical models, offering design guidelines for engineering nanoparticles capable of effectively penetrating mucus barriers. Ultimately, this work contributes to advancing inhaled drug delivery technologies for pulmonary diseases.