Niu Jintong, Zhu Junjie, Li Zhilei, Wang Hong, Gao Yi, Wei Bangguo, Li Youyuan, Wang Huichao, Qian Yechang, Jing Guoxin, Li Li, Wang Shilong
Research Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, PR China; Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, PR China.
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, PR China.
J Control Release. 2025 Aug 28;387:114175. doi: 10.1016/j.jconrel.2025.114175.
Inflammatory bowel disease (IBD) is an autoimmune disease with a long course, numerous complications, and high disability, and its incidence continues to grow worldwide. microRNA-29a (miR-29a) has the potential to regulate inflammation and fibrosis. However, identifying the targets and designing suitable delivery vectors remain major obstacles in the development of miRNA-based drugs. Layered double hydroxide (LDH), which has the biological function of suppressing immune response, is an excellent miRNA carrier. In this study, miR-29a was enclosed in LDH, which enhanced the transfection efficiency and extended the residence of miR-29a in tissues. With elevated lipopolysaccharide (LPS) concentration, LDH@miR-29a showed better inhibition of inflammatory factors and reactive oxygen species in bone marrow-derived macrophages than LDH alone. In addition, the pro-fibrotic effect of transforming growth factor-β1 (TGF-β1) was reduced in NIH-3 T3 cells incubated with LDH@miR-29a. Transcriptome sequencing indicated that LDH@miR-29a significantly decreased Sgk1 and increased the nuclear localization of Foxo3a in both pro-inflammatory and pro-fibrotic environments, suggesting that Sgk1 is a target gene of miR-29a. Furthermore, murine models of colitis and intestinal fibrosis were ameliorated after LDH@miR-29a treatment. These results demonstrate that the Sgk1 and FoxO signaling pathways play important roles in the mechanism of nanocomplexes. This work shows that combining LDH with miR-29a, provides a simultaneous anti-inflammatory and anti-fibrotic approach for treating of IBD.
炎症性肠病（IBD）是一种病程长、并发症多且致残率高的自身免疫性疾病，其发病率在全球范围内持续上升。微小RNA-29a（miR-29a）具有调节炎症和纤维化的潜力。然而，确定靶点和设计合适的递送载体仍然是基于miRNA的药物开发中的主要障碍。层状双氢氧化物（LDH）具有抑制免疫反应的生物学功能，是一种优良的miRNA载体。在本研究中，miR-29a被包裹在LDH中，这提高了转染效率并延长了miR-29a在组织中的停留时间。随着脂多糖（LPS）浓度的升高，与单独的LDH相比，LDH@miR-29a对骨髓来源的巨噬细胞中的炎症因子和活性氧具有更好的抑制作用。此外，在用LDH@miR-29a孵育的NIH-3 T3细胞中，转化生长因子-β1（TGF-β1）的促纤维化作用降低。转录组测序表明，在促炎和促纤维化环境中，LDH@miR-29a均显著降低Sgk1并增加Foxo3a的核定位，表明Sgk1是miR-29a的靶基因。此外，LDH@miR-29a治疗后，小鼠结肠炎和肠道纤维化模型得到改善。这些结果表明，Sgk1和FoxO信号通路在纳米复合物的作用机制中发挥重要作用。这项工作表明，将LDH与miR-29a结合，为治疗IBD提供了一种同时抗炎和抗纤维化的方法。
