Biofabrication of 3D bioprinted and organ-on-chip blood–brain barrier models using hCMEC/D3 for intranasal delivery of central nervous system therapeutics

Abstract The BBB remains a major obstacle to effective treatment of CNS disorders by limiting the entry of most therapeutics into the brain. The hCMEC/D3 is widely used as an in vitro model to study BBB structure, permeability, and drug transport. In parallel, intranasal administration has gained prominence as a non-invasive route to bypass the BBB and deliver therapeutics directly to the brain via olfactory and trigeminal pathways. This review critically explores how hCMEC/D3 models support the development of intranasal N2B drug delivery strategies. Advances in co-culture systems, 3D constructs, and microfluidic BBB-on-chip platforms have improved the physiological relevance of hCMEC/D3. Integration with nasal epithelial models, including ALI cultures and nasal-on-chip systems, enables simulation of the entire N2B transport route. Emerging delivery systems, including mucoadhesive nanoparticles, ligand-targeted carriers, and prodrugs, are evaluated for their performance in dual-barrier in vitro models. While progress is evident, challenges remain in translatability and standardisation. Future efforts integrating omics, machine learning, and organ-on-chip technologies will enhance predictive modelling and accelerate CNS drug development.