Untangling Mucosal Drug Delivery: Engineering, Designing, and Testing Nanoparticles to Overcome the Mucus Barrier

Abstract

Mucus is a complex viscoelastic gel and acts as a barrier covering much of the soft tissue in the human body. High vascularization and accessibility have motivated drug delivery to various mucosal surfaces; however, these benefits are hindered by the mucus layer. To overcome the mucus barrier, many nanomedicines have been developed, with the goal of improving the efficacy and bioavailability of drug payloads. Two major nanoparticle-based strategies have emerged to facilitate mucosal drug delivery, namely, mucoadhesion and mucopenetration. Generally, mucoadhesive nanoparticles promote interactions with mucus for immobilization and sustained drug release, whereas mucopenetrating nanoparticles diffuse through the mucus and enhance drug uptake. The choice of strategy depends on many factors pertaining to the structural and compositional characteristics of the target mucus and mucosa. While there have been promising results in preclinical studies, mucus−nanoparticle interactions remain poorly understood, thus limiting effective clinical translation. This article reviews nanomedicines designed with mucoadhesive or mucopenetrating properties for mucosal delivery, explores the influence of site-dependent physiological variation among mucosal surfaces on efficacy, transport, and bioavailability, and discusses the techniques and models used to investigate mucus−nanoparticle interactions. The effects of non-homeostatic perturbations on protein corona formation, mucus composition, and nanoparticle performance are discussed in the context of mucosal delivery. The complexity of the mucosal barrier necessitates consideration of the interplay between nanoparticle design, tissue-specific differences in mucus structure and composition, and homeostatic or disease-related changes to the mucus barrier to develop effective nanomedicines for mucosal delivery.

Mechanistic Influence of Polymer Species, Molecular Weight, and Functionalization on Mucin–Polymer Binding Interactions

“…The DISCO Effect ( t ) (eq S2) is calculated for all protons at each saturation time point to create buildup curves, which provides relative information regarding proton proximity to the mucin-binding site, regardless of whether the resulting interaction was significant. Understanding the influence of noninteractive polymer functional groups on neighboring polymer functional groups that do exhibit polymer–mucin interactions is expected to help elucidate the cooperative nature of mucoadhesion …”

“…Drug delivery systems that target mucosal surfaces have the potential to improve both patient compliance and therapeutic outcomes . This potential is derived from several performance advantages that can be leveraged by mucosal delivery such as: bypassing first-pass clearance, long-term retention for continuous release, and the reduction of side effects associated with high initial dose. , Mucus is a viscous, heterogeneous, and complex mixture composed in large part of water (95%) and mucin glycoproteins (2–5% w/v) . The remaining components are a balance of lipids, DNA, proteins, and cellular debris .…”

“…One common approach for generating mucoadhesive materials is to imbue their surfaces with a net positive charge, which interacts with the net negative mucin surface via sialic acid residues. Conversely, mucopenetrating materials are typically designed with a net negative or neutral surface charge . Mucoadhesion may also be achieved by exploiting several other nonspecific intermolecular interactions such as hydrogen bonding, chain interpenetration, van der Waals forces, or specific covalent binding such as in the case of disulfide linkages or boron–diol coupling .…”

“…Conversely, mucopenetrating materials are typically designed with a net negative or neutral surface charge . Mucoadhesion may also be achieved by exploiting several other nonspecific intermolecular interactions such as hydrogen bonding, chain interpenetration, van der Waals forces, or specific covalent binding such as in the case of disulfide linkages or boron–diol coupling . Indeed, the strategies for developing and characterizing new mucoadhesive materials are the subject of ongoing research and were recently the feature of comprehensive review .…”

Hydrogel–metal-organic-framework hybrids mediated efficient oral delivery of siRNA for the treatment of ulcerative colitis

“…However, free siRNA released in the colon from sodium alginate particles fail to penetrate the mucosal layer of the inflammatory colon effectively and will be cleared eventually, reducing the therapeutic effect of siRNA. MOF has the potential to permeate the mucosal layer of inflammatory sites, and the only thing that needs to be addressed is degradation in the gastric acid environment [ 29 ]. Thus, they were able to complement each other and successfully deliver a high dose of siRNA to the inflammatory colon.…”