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

Mucus is a complex viscoelastic gel and acts as a barrier covering much of the soft tissue in the human body. Highvascularization and accessibility have motivated drug delivery tovarious mucosal surfaces; however, these benefits are hindered bythe mucus layer. To overcome the mucus barrier, manynanomedicines have been developed, with the goal of improvingthe efficacy and bioavailability of drug payloads. Two majornanoparticle-based strategies have emerged to facilitate mucosaldrug delivery, namely, mucoadhesion and mucopenetration.Generally, mucoadhesive nanoparticles promote interactions withmucus for immobilization and sustained drug release, whereasmucopenetrating nanoparticles diffuse through the mucus andenhance drug uptake. The choice of strategy depends on manyfactors pertaining to the structural and compositional characteristics of the target mucus and mucosa. While there have beenpromising results in preclinical studies, mucus-nanoparticle interactions remain poorly understood, thus limiting effective clinicaltranslation. 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-homeostaticperturbations on protein corona formation, mucus composition, and nanoparticle performance are discussed in the context ofmucosal delivery. The complexity of the mucosal barrier necessitates consideration of the interplay between nanoparticle design,tissue-specificdifferences in mucus structure and composition, and homeostatic or disease-related changes to the mucus barrier to develop effective nanomedicines for mucosal delivery

Automated summary

Mucus serves as a barrier in the human body, hindering drug delivery despite its vascularization and accessibility. Nanoparticle strategies for mucosal drug delivery include mucoadhesion and mucopenetration, depending on mucus and mucosa characteristics. While progress has been made, the understanding of mucus-nanoparticle interactions remains limited for effective clinical translation.