Hydration Driven Nanocarrier Design for Enhanced Mucosal Drug Transport

Mucosal drug delivery has emerged as a promising strategy for both local and systemic therapeutic administration due to its non-invasive nature and extensive absorptive surface area. However, the protective mucus barrier, composed of highly viscoelastic and adhesive mucin networks, significantly restricts the efficient transport of conventional nanocarriers. Traditional mucoadhesive systems, while improving retention, often suffer from limited diffusion and heterogeneous drug distribution across mucosal surfaces. In recent years, hydration driven nanocarrier design has gained substantial attention as an advanced approach to overcome mucus associated transport limitations. Surface hydration layers formed through the incorporation of highly hydrophilic polymers, zwitterionic materials, and biomimetic coatings create a water rich interfacial barrier that minimizes adhesive interactions between nanoparticles and mucin fibers. This hydration mediated lubrication facilitates rapid nanoparticle diffusion, enhances mucus penetration, and improves drug bioavailability. This review critically examines the fundamental mechanisms governing hydration layer formation and its role in modulating nanoparticle mobility across mucosal barriers. The physicochemical characteristics of mucus, including structural heterogeneity, rheological behavior, and disease induced alterations, are discussed to provide a comprehensive understanding of transport challenges. Various material engineering strategies for generating stable hydration layers, along with fabrication techniques and characterization methodologies, are systematically reviewed. Particular emphasis is placed on the translational potential of hydration driven nanocarriers in oral and pulmonary drug delivery, highlighting their ability to enhance drug stability, absorption, and targeted delivery. Additionally, safety considerations, regulatory challenges, and manufacturing limitations associated with hydration engineered nanocarriers are analyzed. The review concludes by outlining emerging trends such as adaptive surface engineering and personalized mucosal nanomedicine, underscoring the future potential of hydration based nanocarrier systems in overcoming biological barriers and improving therapeutic outcomes.