HS15-based nanotherapeutics for direct nose-to-brain delivery against central nervous system fungal

Amphotericin B (AmB) is a broad-spectrum antifungal drug, but its use in the treatment of fungal infections in the central nervous system (CNS) has been limited by the constraints of the blood-brain barrier (BBB) and the severe toxicity of systemic administration. Nose-to-brain administration, as a non-invasive strategy, may bypass the BBB and deliver drugs to the brain via the olfactory or trigeminal pathways, increasing intracerebral drug concentrations while reducing systemic side effects. Therefore, this study constructed a nanocomplex carrier based on HS15, lecithin and cholesterol (HS15-LC) to deliver AmB to the brain via intranasal administration to explore the feasibility of nasal-brain delivery of AmB. Using encapsulation efficiency as an indicator, the optimal HS15-LC formulation was screened out, and its particle size and potential were determined. The results showed that the particle size and potential remained stable before and after loading. The stability test showed that the nasal spray had good stability in placement, dilution, and spraying. The results of releasing in vivo and imaging in vitro showed that the formulation was able to provide a longer and higher intracerebral distribution. Histopathological analyses confirmed that there were minimal mucosal toxicity and nephrotoxicity during nose-to-brain administration. In conclusion, nose-to-brain administration of AmB is a promising strategy for the treatment of fungal infections in the CNS, combining both brain-targeting and safety advantages, and providing new ideas for the treatment of clinically refractory fungal meningitis.