Intranasal mucoadhesive biomaterials for nose-to-brain neuroactive delivery: platform design and model-informed translation for time-bounded CNS exposure

Intranasal nose-to-brain delivery remains difficult to translate because regional deposition, mucociliary clearance, epithelial transport, local instability, tolerability feedback, and systemic absorption jointly determine central nervous system (CNS) exposure. This evidence-mapping review evaluates mucoadhesive biomaterial platforms as formulation-development tools for improving residence, release control, deposition reproducibility, and exposure interpretability in neuroactive intranasal delivery, using insomnia-relevant timing requirements as a stringent case for controlled onset and offset. PubMed/MEDLINE, Embase, Web of Science Core Collection, and Scopus were searched from 1 January 2008 to 30 April 2026. Seventeen primary intranasal platform studies were included; route-attribution credibility was high in five studies, moderate in five, low in six, and not assessable in one. Platform classes included in situ gelling depots, pre-formed gels, polymeric nanoparticles, lipid or vesicular carriers, hybrid nanoparticle-in-gel systems, and device-coupled dry powders. Key formulation variables were translated into development endpoints, including rheology, gelation, mucoadhesion, release kinetics, deposition, permeability, systemic leakage, and nasal tolerability. The proposed model-informed strategies are conceptual; no new physiologically based pharmacokinetic simulations were performed. Successful platforms should be judged by reproducible onset, controlled offset, bounded systemic exposure, and recovery-phase safety rather than by peak brain concentrations or targeting ratios alone.