Highly viscoelastic human mucus layers protect the lungs, GI tract, reproductive tract, eye and more from infectious pathogens and foreign particulates. The human mucus barrier was recently reported as impermeable to polymer nanoparticles as small as 59 nm. Particles that cannot move through the outer layers of mucus are cleared from the mucosal tissue within seconds to at most a few hours. This reality has strongly limited development of long-lasting controlled release systems to mucus-covered tissues, and likely has played a major role in thwarting gene therapy of mucosal tissues as well.

We hypothesized that adhesion to mucus was a critical rate-limiting barrier to nanoparticle transport through mucus layers. We sought to mimic the hydrophilic and net-neutral surface properties of viruses capable of rapidly moving through human mucus. Our initial search for a candidate material that could endow these surface properties on synthetic particles led us to poly(ethylene-glycol), or PEG. Paradoxically, PEG had a considerable history of use as a muco-adhesive.

Here, we describe our recent discovery that coating synthetic nanoparticles with high densities of low molecular weight PEG allows particles with sizes of at least 500 nm in diameter to rapidly transport through undiluted human mucus nearly as fast as they move through pure water. In contrast, high molecular weight PEG coating makes them even more adhesive to mucus than without coatings. We show that PEG density is especially critical as particle size diminishes from 500- to 100-nm. We also show that the spacings within the human mucus mesh are much larger than previously appreciated, which provides a significant opportunity for controlled drug delivery using large nanoparticles. The already large native mesh spacing can be further manipulated to allow micron-sized particles to penetrate mucus at speeds approaching water. We have further show that we can engineer mucus penetrating particles, using a variety of biomaterials, to rapidly penetrate various other human mucus secretions. Animal studies using MPP for gene therapy of the lungs as well as localized and sustained cancer therapy in mucosal tissues are underway.