Testing Bound-State Diffusion as a Model for Mucosal Transport of Nanoparticles

Mucus, which covers a variety of tissues, has proven to be a formidable barrier to the delivery of therapeutics to epithelial surfaces. Nanoparticles have been proposed as a platform for mucus penetration; however, it has typically been seen that particles that interact weakly with the mucus can be easily washed away when the surrounding fluid is exchanged, while those that bind to the mucus tightly may have limited mobility and be unable to reach the cell surface. We recently hypothesized a theoretical framework that overcomes both restraints through a process we termed bound-state diffusion. Specifically, we posit that particles designed with two elements, transient binding and flexible tethers, will allow motion while bound. Here, we test this hypothesis using bacteriophage-based nanoparticles decorated with hyaluronic acid (HA), which has long been known to be retained in mucus through hydrogen bonding and hydrophobic interactions. We show that nanoparticles decorated with long HA polymers (10 and 50 kDa) retain significant mobility within mucus even though HA is known to bind to mucus. This seemingly contradictory result can be understood through our bound-state diffusion hypothesis. Further, we show that particles co-decorated with HA and MVASI, an antibody used in a variety of angiogenic cancer settings, retain both muco-diffusive properties and biological activity of the antibody. Our results demonstrate the feasibility of using bound-state diffusion in nanoparticle design for the delivery of biologics through mucosal barriers.