Gao Qiongqiong, Zhang Jing, Chen Chen, Chen Menglin, Sun Peng, Du Wei, Zhang Shengchang, Liu Ying, Zhang Rui, Bai Mei, Fan Changchun, Wu Jibiao, Men Tongyi, Jiang Xinyi
Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, Shandong Province, PR China.
Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, PR China.
ACS Nano. 2020 Apr 28;14(4):3980-3990. doi: 10.1021/acsnano.9b07896. Epub 2020 Mar 18.
Deep infection is one of the major causes of death in immunosuppressed hosts. Remodeling macrophages to phenotype M1 can decrease fungus burden and facilitate combating 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 "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- 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 . Therefore, the mannosylated nanotrinity developed in this study could significantly induce macrophage remodeling by the two-pronged process, "turning on" M1 phenotype polarization meanwhile "shutting off" M2 phenotype polarization, and thus allowed to eradicate infection.
深部感染是免疫抑制宿主的主要死亡原因之一。将巨噬细胞重塑为M1表型可以减轻真菌负荷，并有助于在免疫抑制状态下对抗感染。在本研究中，利用巨噬细胞再分化的调控途径，开发了一种纳米三联体来引导巨噬细胞的杀菌极化。常规化疗药物伊马替尼可通过“关闭”STAT6磷酸化途径来消除M2巨噬细胞极化，将其包裹在可生物降解的聚合物纳米颗粒中。然后，将内部定制的双功能甘露糖化壳寡糖包被在载有伊马替尼的纳米颗粒表面，从而获得具有巨噬细胞重塑三元功能的甘露糖化纳米三联体：（i）伊马替尼阻断STAT6磷酸化途径以减少M2巨噬细胞数量；（ii）壳寡糖介导的TLR-4途径激活可促进巨噬细胞再分化为M1表型；（iii）甘露糖基序增强巨噬细胞靶向性。经过理化表征后，分别在细胞水平和动物水平评估了甘露糖化纳米三联体对巨噬细胞的调节作用和抗真菌效果。结果表明，我们的甘露糖化纳米三联体能够有效地诱导巨噬细胞向M1表型极化，减少M2表型的产生，并显著减轻真菌负荷，延长感染小鼠的中位生存时间。因此，本研究中开发的甘露糖化纳米三联体可以通过“开启”M1表型极化同时“关闭”M2表型极化的双管齐下过程，显著诱导巨噬细胞重塑，从而根除真菌感染。
