A "three-in-one" nose-to-brain delivery strategy: intranasal vancomycin spray achieves simultaneous clearance of pneumococcal colonization, bacteremia, and meningitis.

Bacterial meningitis caused by Streptococcus pneumoniae is a lethal central nervous system infection, yet conventional intravenous vancomycin struggles to cross the blood-brain barrier effectively. Interestingly, the natural pathology of this pathogen originates from nasopharyngeal colonization, disseminates into systemic bacteremia, and ultimately breaches the meninges. Inspired by this sequential invasion, we hypothesized that administering vancomycin directly at the exact starting point via a nasal spray could achieve a simultaneous "three-in-one" eradication of all infection stages. To realize this goal and overcome the bottleneck of nasal delivery, we developed a vancomycin nasal spray using hydroxypropyl methylcellulose as a viscosity modifier. By systematically tuning the formulation viscosity, we achieved a synchronous optimization of the macroscopic spray morphology and microscopic droplet behavior. This aerodynamic balance minimized premature droplet impaction at the anterior nasal valve and prevented excessive gravitational settling in the main nasal meatus. Quantitative analysis in a 3D-printed human nasal cast demonstrated that the optimized formulation F4 maximized target site coverage, achieving a total nasal meatus deposition of 2491.7 μg and a peak olfactory deposition fraction of 5.06%. The optimized spray increased cerebrospinal fluid bioavailability by 2.93-fold and drastically reduced peripheral renal exposure by 74.93% compared to intravenous injection. In a pneumococcal infection rat model, the intranasal therapy demonstrated superior multidimensional bactericidal efficacy, clearing 89.81% of the local nasopharyngeal colonies, 97.11% of the systemic bacteremia, and 93.83% of the intracerebral bacterial load. This robust pathogen clearance was accompanied by the prompt resolution of localized neuroinflammation, systemic procalcitonin levels, and circulating leukocyte abnormalities. Ultimately, this aerodynamically engineered formulation provides an anatomically inspired and highly effective intervention paradigm for managing complex central nervous system infections.