Intranasal delivery of engineered macrophage-membrane-coated nanoparticles with enhanced Dectin-1 expression for targeted therapy of cryptococcal meningitis.

Abstract

Cryptococcal meningitis is a devastating fungal infection of the central nervous system that disproportionately affects immunocompromised individuals and carries high mortality. Amphotericin B (AmB), the clinical gold standard, exhibits potent fungicidal activity but is associated with substantial systemic toxicity. Nanoparticle-based delivery systems have been explored to enhance AmB therapeutic efficacy and mitigate systemic toxicity; however, inadequate blood-brain barrier (BBB) penetration and the absence of pathogen-specific targeting remain major obstacles. Herein, we developed a biomimetic targeted nanoplatform for intranasal delivery to address these challenges. The nanoplatform was constructed by coating self-assembled AmB and chlorin e6 (Ce6) hybrid nanoparticles with genetically engineered macrophage membranes overexpressing the β-glucan receptor Dectin-1. Following intranasal administration, the nanoplatform efficiently reached the meninges and specifically bound Cryptococcus neoformans via Dectin-1-mediated recognition, upon which ultrasound stimulation triggered reactive oxygen species (ROS) generation from Ce6 and rapid AmB release. In vitro studies confirmed the enhanced fungal targeting and antifungal efficacy of the engineered nanoplatform. In a murine model of cryptococcal meningitis, treatment with this nanoplatform significantly reduced brain fungal burden, alleviated histopathological damage, and prolonged survival compared with commercially available liposomal AmB. Collectively, these findings highlight the biomimetic targeted nanoplatform as a promising therapeutic strategy for fungal infections in the brain.