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

Abstract

Deep Candida albicans infection is one of the major causes of death in immunosuppressed hosts. Remodeling macrophages to phenotype M1 can decrease fungus burden and facilitate combating C. albicans under an immunosuppressive state. In this study, a nanotrinity was exploited to direct fungicidal macrophage polarization by leveraging the regulation pathways in macrophage redifferentiation. Conventional chemotherapeutic imatinib, which can abrogate M2 macrophage polarization via "shutting off" the 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 redifferentiation to M1 phenotype; (iii) mannose motif-enhanced macrophage targeting. After physiochemical characterization, regulatory effects of the mannosylated nanotrinity on macrophages and the anti-C. albicans efficacy were evaluated at the cellular level and animal level, respectively. The results demonstrated that our mannosylated nanotrinity could efficiently induce macrophage polarization toward the M1 phenotype, decrease M2 phenotype production, and markedly lessen fungus burden and increased the median survival time of mice infected with C. albicans. Therefore, the mannosylated nanotrinity developed in this study could significantly induce macrophage remodeling in situ by the two-pronged process, "turning on" M1 phenotype polarization meanwhile "shutting off" M2 phenotype polarization, and thus allowed to eradicate C. albicans infection.

Keywords: Candida albicans; chitosan oligosaccharides; imatinib; macrophage polarization; mannosylated nanotrinity.