A biomimetic nanovesicle derived from BCG-primed macrophages with mannose modification for targeted immunotherapy against cryptococcal meningitis.

Cryptococcal meningitis is a life-threatening fungal infection of the central nervous system (CNS), characterized by an immunosuppressive microenvironment driven by Cryptococcus neoformans-induced polarization of macrophages toward M2 phenotype, which undermines host immunity and limits the efficacy of conventional antifungal therapies. To address these challenges, we developed a biomimetic mannose-modified nanovesicle (MBNV) system derived from Bacillus Calmette-Guérin (BCG)-primed bone marrow-derived macrophages (BMDMs) for dual action CNS immunotherapy. In vitro and in vivo studies demonstrate that MBNVs efficiently penetrate the blood-brain barrier (BBB), selectively accumulate within infected brain tissues, and specifically target M2-polarized macrophages via mannose receptor recognition. Upon delivery, MBNVs retain immunostimulatory cues from BCG-primed macrophages to effectively reprogram M2 macrophages toward a proinflammatory M1-like phenotype, thus restoring local antifungal immunity. As a proof of concept, we co-loaded the antifungal agent isobavachalcone (IBC) into MBNVs (IBC@MBNVs), achieving synergistic therapeutic effects in vivo. IBC@MBNVs significantly enhance macrophage repolarization, improve intracellular fungal clearance, markedly reduce CNS fungal burden, and extend survival in a murine cryptococcal meningitis model, surpassing the therapeutic efficacy of either component alone. This biomimetic dual functional strategy, integrating targeted immune reprogramming with CNS-targeted antifungal drug delivery, represents a promising and innovative approach to overcome immune evasion and drug delivery barriers in cryptococcal meningitis.