Tailored Borneol-Modified Lipid Nanoparticles Nasal Spray for Enhanced Nose-to-Brain Delivery to Central Nervous System Diseases

The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood–brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery ( R 2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.