Particle size-dependent efficiency and mechanistic insights of nose-to-brain delivery bypassing the BBB

Central nervous system (CNS) diseases remain a therapeutic challenge due to the blood-brain barrier (BBB). The nose-to-brain pathway offers a promising non-invasive route to bypass the BBB, yet the impact of nanocarrier size on this multi-stage delivery process is poorly understood. This study systematically investigated the role of particle size using solid lipid nanoparticles (SLNS) of 80, 120, 240, 360, and 480 nm, formulated into nasal sprays. In vivo imaging in mice revealed a non-monotonic relationship, with 240 nm SLNS (SLNS3) achieving peak brain accumulation via both olfactory and trigeminal pathways, approximately 1.7-fold higher than other sizes. In vitro models deconstructing the delivery cascade showed that while smaller particles (80 nm) penetrated mucus and nasal epithelium more efficiently, the 240 nm SLNS exhibited superior uptake by neuronal cells and unparalleled transcytosis efficiency to microglia and glioma cells. Mechanistic studies unveiled that SLNS3 uniquely exploited multiple endocytic pathways (clathrin, caveolae, and macropinocytosis) for entry and was preferentially trafficked to the endoplasmic reticulum and Golgi apparatus, facilitating transcellular transport. The superior nose-to-brain delivery efficiency of 240 nm SLNS3 was also validated by a glioma model. Together, our findings pinpoint 240 nm as an optimal size within the SLNS system, reveal the governing cellular mechanisms, and provide a valuable reference for the rational design of nose-to-brain nanomedicines.