负载ZM-029的M1-exosomes靶向协同调控巨噬细胞极化治疗肝纤维化的研究

肝纤维化是严重的全球性健康难题，目前缺乏有效的治疗方法，定向调控巨噬细胞极化是治疗肝纤维化的新策略。本课题组前期研究发现回输M1型巨噬细胞exosomes能有效诱导M1极化，抗肝纤维化疗效优于回输M1型巨噬细胞。为进一步提高疗效，构建M1-exosomes-ZM-029治疗体系，即M1-exosomes装载前期筛选的抗肝纤维化小分子化合物ZM-029，克服其水溶性和靶向性差的缺陷，发挥高效协同靶向抗肝纤维化效应。初步研究提示该体系通过调控H3K27翻译后修饰介导JAK1/STAT6/KLF4通路，促进M1极化，发挥抗肝纤维化效用。本课题组拟采用多组学联合分析、结合分子及细胞生物学层面的功能验证实验，阐明M1-exosomes-ZM-029治疗体系调控巨噬细胞极化，改善肝纤维化的分子机制，并在构建该治疗体系基础上拓展exosomes作为药物载体的普适性应用，评价其潜在的临床转化应用价值。

Hepatic fibrosis is a severe global health problem. There are few valid therapeutic methods to reverse hepatic fibrosis, while the orientation regulation of macrophage polarization is the new strategy for treatment of hepatic fibrosis. In the preliminary study, our group found that M1 polarization can be induced by transfusing back M1 macrophage exosomes, has a better therapeutic effect than transfusing back M1 macrophage. In order to further improve the therapeutic effect, we constructed M1-exosomes-ZM-029 therapeutic system by loading ZM-029, a small molecule compound of anti-hepatic fibrosis selected in the early investigation, into M1-exosomes. It can overcome the poor water solubility and non-targeting ability defects of ZM-029, and exert high-efficient effect of target coordinated anti-hepatic fibrosis. According to the preliminary study, this system prompts M1 polarization and exerts the effect of anti-hepatic fibrosis through regulating H3K27 post-translational modification mediate JAK1/STAT6/KLF4 pathway. Through adopting the joint analysis of multi-omics in combination with functional verification experiments of molecule and cell biology, we plan to dig M1-exosomes-ZM-029 therapeutic system deeper, in view of regulating macrophage polarization, and reversing hepatic fibrosis. Expanding the general application of exosomes as a natural drug carrier based on building M1-exosomes-ZM-029 therapeutic system, and further determine the clinic conversion application value of the therapeutic system.