荷载miR-155纳米颗粒靶向肿瘤相关巨噬细胞抑制SOCS1表达促使巨噬细胞重构治疗乳腺癌

Tumor-associated macrophages play an important role in tumor microenvironment. The bad prognosis is closely related to the enrichment of tumor-associated macrophages in breast cancer. Tumor-associated macrophages are considered M2 type macrophages, which can promote cancer growth, invasion, and metastasis. This project aims to develop nanoparticles targeting tumor-associated macrophages, combining with active targeting feature of nanoparticles, to deliver miR-155 into tumor-associated macrophages to inhibit SOCS1 protein. This can reprogram the macrophages from M2 type to M1 type, which can kill the cancer cell and inhibit development of cancer. First, we develop the mannose-linked nanoparticles for the delivery of miRNA targeting tumor-associated macrophages that expressing CD206. Second, to observe the marker of tumor-associated macrophages and the cell factors secreted by tumor-associated macrophages after treated with miR-155 delivered by nanoparticles in vitro, and then co-cultures with breast cancer cells. Finally, to explore the reprograming effect of tumor-associated macrophages in breast cancer in vivo, tumor-associated macrophages and breast cancer cells were co-implanted to nude mice or 4T1 breast cancer cells implanted in Balb/C mice, and then treated with miR-155 delivered by nanoparticles. This project offers a new immunotherapy method for us to reprogram tumor-associated macrophages for breast cancer treatment.

肿瘤相关巨噬细胞在肿瘤微环境中发挥着极其重要的作用。肿瘤相关巨噬细胞认为是M2型巨噬细胞，能促进肿瘤的生长、侵袭和转移。本项目开发主动靶向肿瘤相关巨噬细胞纳米材料，输送miR-155进入巨噬细胞抑制SOCS1蛋白。这可重构M2型巨噬细胞成为M1型巨噬细胞，从而杀死肿瘤细胞，抑制肿瘤生长。我们开发甘露糖链接纳米材料用于荷载miRNA靶向表达CD206的肿瘤相关巨噬细胞。在体外实验，采用纳米材料荷载miR-155处理肿瘤相关巨噬细胞，观察巨噬细胞的表面标记物和分泌的细胞因子的情况，进而观察巨噬细胞与肿瘤细胞共培养情况。最后在体内实验，将肿瘤相关巨噬细胞与乳腺癌细胞共植入裸鼠体内或4T1乳腺癌细胞植入Balb/C小鼠体内，然后采用纳米材料荷载miR-155治疗，探讨重构肿瘤相关巨噬细胞对肿瘤细胞杀伤及抑制肿瘤生长作用。这个项目为我们提供了一种通过重构肿瘤相关巨噬细胞治疗乳腺癌的免疫治疗新方法。

肿瘤相关巨噬细胞在肿瘤微环境中发挥着极其重要的作用。肿瘤相关巨噬细胞认为是M2型巨噬细胞，能促进肿瘤的生长、侵袭和转移。本项目建立了NP纳米颗粒平台，能很好结合、携带及释放RNA，能够荷载RNA进入巨噬细胞内，有效沉默M2型巨噬细胞，并且证明大粒径NP颗粒（NP-180）能更有效被巨噬细胞内吞和沉默目标基因。我们构建了这种可以调控尺寸的纳米颗粒体系，并证实特定尺寸纳米颗粒可有效转载目标RNA发挥巨噬细胞的基因抑制功能。后续我们计划将此纳米载药系统用于巨噬细胞给药，调控不同器官的微环境。