BBB modulation-driven potentiation of antifungal therapy by melittin in fungal encephalitis.

Effective management of fungal encephalitis is constrained by the dual challenge of restricted drug penetration across the blood-brain barrier (BBB) and the inability of conventional antifungal agents to control infection-associated neuroinflammation. In this study, we evaluated melittin (MLT), an amphipathic membrane-active peptide, as a multifunctional therapeutic candidate. In vitro studies confirmed MLT directly inhibited C. albicans growth and attenuated virulence gene expression. Using dual-modal fluorescence and magnetic resonance imaging (MRI), we demonstrated that MLT reversibly and dose-dependently enhances BBB permeability, a critical precondition for central nervous system access. In a murine model of C. albicans-induced fungal encephalitis, MLT outperformed conventional antifungal treatment not only in reducing fungal burden but also in potently suppressing neuroinflammatory responses. Our findings establish MLT as a therapeutic agent that uniquely integrates BBB regulation with pathogen clearance and immunomodulation, offering a coordinated strategy to overcome the core limitations of current antifungal therapies for fungal encephalitis.