Zeng Zhiying, Li Changying, Liu Ye, Chen Hui, Feng Xuli
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Innovative Drug Research Centre, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
ACS Appl Bio Mater. 2023 Mar 20;6(3):1306-1312. doi: 10.1021/acsabm.3c00094. Epub 2023 Mar 7.
Oxidative stress caused by the overproduction of reactive oxygen species (ROS) plays an important role in inflammatory bowel disease (IBD). It is well-known that the Nrf2-ARE (antioxidative response element) pathway is important in the regulation mechanism of antioxidant defense. Therefore, Nrf2 activation may be an effective therapeutic strategy for IBD. Here, we reported the development of a nucleus-targeted Nrf2 delivery nanoplatform, termed N/LC, that could accumulate in inflamed colonic epithelium, reduce inflammatory responses, and restore epithelium barriers in a murine model of acute colitis. N/LC nanocomposites could quickly escape from lysosomes, so Nrf2 largely accumulated in the nucleus of colonic cells, activated the Nrf2-ARE signaling pathway, further elevated the expression levels of downstream detoxification and antioxidant genes, and protected cells from oxidative damage. These results suggested that N/LC might be a potential nanoplatform for IBD therapy. The study provided the basis for the biomedical applications of Nrf2-based therapeutics in various diseases.
活性氧（ROS）过量产生所引起的氧化应激在炎症性肠病（IBD）中起重要作用。众所周知，Nrf2-抗氧化反应元件（ARE）通路在抗氧化防御调节机制中至关重要。因此，激活Nrf2可能是治疗IBD的一种有效策略。在此，我们报道了一种靶向细胞核的Nrf2递送纳米平台N/LC的研发，该纳米平台可在急性结肠炎小鼠模型的炎症结肠上皮中蓄积，减轻炎症反应并恢复上皮屏障。N/LC纳米复合材料能够快速从溶酶体中逃逸，因此Nrf2大量蓄积在结肠细胞的细胞核中，激活Nrf2-ARE信号通路，进一步提高下游解毒和抗氧化基因的表达水平，并保护细胞免受氧化损伤。这些结果表明，N/LC可能是一种治疗IBD的潜在纳米平台。该研究为基于Nrf2的疗法在各种疾病中的生物医学应用提供了依据。
