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Published on: April 29, 2015
A biomimetic nanovesicle derived from BCG-primed macrophages with mannose modification for targeted immunotherapy
Yanqiang Huang1, Lei Lei2, Lingli Huang1
1Guangxi Technology Innovation Cooperation Base of Prevention and Control Pathogenic Microbes with Drug Resistance; Key Laboratory of the Prevention and Treatment of Drug Resistant Microbial Infecting, Education Department of Guangxi Zhuang Autonomous Region, Youjiang Medical University for Nationalities, Baise 533000, China.
Abstract:
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.
Insights
This study introduces biomimetic nanovesicles that reprogram immune cells in the brain to fight fungal infections like cryptococcal meningitis. These nanovesicles, loaded with an antifungal drug, show promise for treating this serious CNS infection.
Area of Science:
- Neuroscience
- Immunology
- Biomedical Engineering
Background:
- Cryptococcal meningitis is a severe fungal infection of the central nervous system (CNS).
- The infection creates an immunosuppressive environment by polarizing macrophages to an M2 phenotype, hindering host immunity and conventional treatments.
- Effective therapies are limited by immune evasion and challenges in delivering drugs to the CNS.
Purpose of the Study:
- To develop a novel biomimetic mannose modified nanovesicle (MBNV) system for dual-action CNS immunotherapy against cryptococcal meningitis.
- To investigate the ability of MBNVs to penetrate the blood-brain barrier (BBB), target M2 macrophages, and reprogram them to an M1-like phenotype.
- To evaluate the synergistic therapeutic potential of MBNVs co-loaded with an antifungal agent.
Main Methods:
- Development of MBNVs from Bacillus Calmette-Guérin (BCG)-primed bone marrow-derived macrophages (BMDMs).
- In vitro and in vivo studies to assess BBB penetration, selective accumulation in infected brain tissue, and M2 macrophage targeting via mannose receptor recognition.
- Co-loading of isobavachalcone (IBC) into MBNVs (IBC@MBNVs) for combination therapy.
Main Results:
- MBNVs demonstrated efficient BBB penetration and selective accumulation in infected CNS tissues.
- MBNVs successfully reprogrammed M2 macrophages to an M1-like phenotype, restoring local antifungal immunity.
- IBC@MBNVs exhibited synergistic therapeutic effects, significantly enhancing macrophage repolarization, improving fungal clearance, reducing fungal burden, and extending survival in a murine model.
Conclusions:
- The developed biomimetic nanovesicle system offers a promising strategy for overcoming immune evasion and drug delivery barriers in cryptococcal meningitis.
- This dual-functional approach, combining targeted immune reprogramming with CNS-targeted antifungal delivery, represents an innovative therapeutic avenue.
- IBC@MBNVs significantly improved therapeutic outcomes compared to individual components, highlighting their potential for treating this life-threatening infection.
