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In Situ Mannosylated Nanotrinity-Mediated Macrophage Remodeling Combats Candida albicans Infection.

Deep Candida albicans infection is one of the major causes of death in immunosuppression host. Remodeling macrophages to phenotype M1 can decrease fungus burden and facilitate combating Candida albicans under immunosuppressive state. In this study, a nanotrinity was exploited to direct fungicidal macrophage polarization by leveraging the regulation pathways in macrophage re-differentiation. Conventional chemotherapeutic imatinib which can abrogate M2 macrophage polarization via "shutting off" STAT6 phosphorylation pathway, was encapsulated in biodegradable polymeric nanoparticles. In house-customized dual functional mannosylated chitosan oligosaccharides were then coated on the surface of the imatinib-laden nanoparticles, and thus a mannosylated nanotrinity was achieved with ternary functions for macrophage remodeling: (i) imatinib-blocked STAT6 phosphorylation pathway for decreasing M2 macrophage population; (ii) chitosan oligosaccharides-mediated TLR-4 pathway activation that could promote macrophage re-differentiation to M1 phenotype; (iii) mannose motif-enhanced macrophage targeting. After physiochemical characterization, regulatory effects of the mannosylated nanotrinity on macrophages and the anti-Candida albicans efficacy were evaluated at cellular level and animal level respectively. The results demonstrated our mannosylated nanotrinity could efficiently induce macrophage polarization towards M1 phenotype and decrease M2 phenotype production, and markedly lessen fungus burden and increased the median survival time of the mice infected with Candida albicans. Therefore, the mannosylated nanotrinity developed in this study could significantly induce macrophages remodeling in situ by the two-pronged process: "turning on" M1 phenotype polarization meanwhile "shutting off" M2 phenotype polarization, and thus allowed to eradicate Candida albicans infection.