Advances in Intranasal CNS Targeting: Integrating Formulations, Devices, Computational Fluid Dynamics, and 3D Printing

Nose-to-brain (N2B) delivery is a practical, non-invasive strategy for CNS targeting that can increase brain exposure while limiting systemic exposure. This review integrates three milestones in N2B delivery, formulations, devices, and quantitative evaluation strategies, to define design rules for effective olfactory/trigeminal deposition and enhance translational relevance. Formulations emphasize mucoadhesive systems, nanoparticle carriers (polymeric, lipid-based, and hybrid), nano-emulsions, and stimuli-responsive "smart" gels that prolong nasal residence. Regarding device advancements, the review covers conventional nasal sprays optimized for plume geometry and droplet size. Furthermore, it examines breath-actuated metered sprays, which promote soft palate closure to route aerosols to superior regions, and vibrating mesh nebulizers capable of low-velocity mists for improved upper cavity deposition. Quantitative evaluation is discussed, including 3D-printed, anatomy-accurate nasal casts, high-speed spray diagnostics, and computational fluid dynamics (CFD). This review further links formulation and device parameters to regional deposition. Available clinical and animal data illustrate the feasibility of these approaches, safety considerations, and user-technique dependencies, while highlighting the need for standardized, anatomy-aware testing protocols. Together, these developments suggest that co-designed formulation device platforms, validated by cast/CFD metrics and supported by clinical imaging or pharmacokinetic data, can support N2B product development toward consistent, patient-relevant outcomes.