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.

Artificial Engineering of Immune Cells for Improved Immunotherapy

“…Gao et al designed a mannosylated nanotrinity to in vivo manipulate in situ macrophages for treating Candida albicans infection. [ 46 ] Decoration of mannose promoted the specific internalization of nanotrinity in macrophages. Imatinib and chitosan oligosaccharides were embedded into polymeric nanotrinity for not only inhibiting M2 polarization but also activating macrophages’ transformation into pro‐inflammatory M1 phenotype (Figure 2d).…”

“…Imatinib and chitosan oligosaccharides were embedded into polymeric nanotrinity for not only inhibiting M2 polarization but also activating macrophages’ transformation into pro‐inflammatory M1 phenotype (Figure 2d). [ 46 ] Synergism between inhibiting M2 phenotype and stimulating M1 polarization led to robust macrophage‐mediated fungicidal effect.…”

Neutrophils and Macrophages as Targets for Development of Nanotherapeutics in Inflammatory Diseases

“…It should be noted that transition to the anti-inflammatory phenotype (M2) is not universal for anti-inflammation. For example, in a severe infection, nanoparticles that promoted the activation of M1, but inhibited the M2 phenotype showed an anti-infection benefit [138]. This dilemma between M1 and M2 in anti-inflammation requires further investigation.…”

Studying bone marrow-derived macrophages needs to consider the influence of cells apart from macrophage, especially the selection of markers

“…The timely shifting from M1 towards the M2 phenotype of Macrophage is usually concerned with tissue repair. In contrast, Gao et al mentioned that an opposite strategy was needed for tackling Candida albicans with the demand effectively to improve the survival rate after being infected 1 . To evaluate the nano-trinity treatment effect on phenotypes of macrophage and its expression, flow, western blot (WB), and ELISA kits were adopted.…”

“…addition, as recommended by Gao et al, increasing M1 macrophages can promote the expression of NO, ROS and enhance phagocytosis to fight candida albicans1 , however, candida albicans may end up resulting in the death of macrophages by transferring its metabolic way on glucose that macrophage could rival it7 . Thus, to confirm that macrophages can reduce the damage of Candida by enhancing M1 macrophage polarization, longer-term observation is needed.…”