Sun Yao, Cai Shihao, Liu Hongting, Zhao Conglu, Xu Xiang, Wang Xiaoting, Zhang Jia, Zheng Chaoyue, Li Keran, Peng Shouchun, Zhou Honggang, Xu Aiguo, Gu Xiaoting, Ai Xiaoyu, Yang Cheng
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, PR China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, PR China.
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, PR China.
Int J Pharm. 2025 Aug 20;681:125750. doi: 10.1016/j.ijpharm.2025.125750. Epub 2025 May 31.
Idiopathic pulmonary fibrosis (IPF) is characterized by symptoms such as shortness of breath, persistent dry cough, and hypoxemia. The disease can progress rapidly, often leading to respiratory failure. Given its complex and multifactorial nature, pulmonary fibrosis involves multiple pathological progress, such as inflammation, oxidative stress, and fibroblast activation. A single drug cannot effectively address pulmonary fibrosis through multiple mechanisms, but combining drugs maybe create a synergistic effect, target different aspects of the pathological process and improve treatment efficacy. In our previous study, bergenin can improve pulmonary fibrosis. Vitexin is reported to have anti-inflammatory, antioxidant, and anticancer properties, which maybe influence pathways associated with pulmonary fibrosis. Therefore, bergenin and vitexin were chosen for the combined treatment of pulmonary fibrosis. To improve the targeting ability and the affinity of lung fibroblasts, mouse lung fibroblasts-derived exosomes are used as the carriers for drugs. In this study, exosomes loaded with bergenin and vitexin (Exo-Ber + Vit) were successfully prepared using ultracentrifugation and ultrasonication, with an average particle size of approximately 180 nm. Wound-healing assay showed that Exo-Ber + Vit significantly inhibited the excessive proliferation of TGF-β1 induced Mlg and NIH-3 T3 cells compared with bergenin and vitexin alone. Cell uptake experiments showed that exosomes enhanced the uptake of coumarin 6 in Mlg and 3 T3 cells. In vivo studies, compared to bergenin-loaded exosomes, vitexin-loaded exosomes, and the combination of bergenin and vitexin, Exo-Ber + Vit demonstrated superior effects in reducing pulmonary fibrosis area, collagen deposition, and improving lung function. In conclusion, the co-delivery strategy of bergenin and vitexin via Mlg-derived exosomes offers a promising new approach to the treatment of IPF.
特发性肺纤维化（IPF）的特征表现为呼吸急促、持续性干咳和低氧血症等症状。该疾病进展迅速，常导致呼吸衰竭。鉴于其复杂的多因素性质，肺纤维化涉及多种病理过程，如炎症、氧化应激和成纤维细胞活化。单一药物无法通过多种机制有效治疗肺纤维化，但联合用药可能产生协同效应，针对病理过程的不同方面并提高治疗效果。在我们之前的研究中，岩白菜素可改善肺纤维化。据报道，牡荆素具有抗炎、抗氧化和抗癌特性，这可能影响与肺纤维化相关的途径。因此，选择岩白菜素和牡荆素联合治疗肺纤维化。为提高对肺成纤维细胞的靶向能力和亲和力，将小鼠肺成纤维细胞来源的外泌体用作药物载体。在本研究中，通过超速离心和超声处理成功制备了负载岩白菜素和牡荆素的外泌体（Exo-Ber + Vit），平均粒径约为180 nm。伤口愈合试验表明，与单独使用岩白菜素和牡荆素相比，Exo-Ber + Vit显著抑制了TGF-β1诱导的Mlg和NIH-3 T3细胞的过度增殖。细胞摄取实验表明，外泌体增强了Mlg和3 T3细胞对香豆素6的摄取。在体内研究中，与负载岩白菜素的外泌体、负载牡荆素的外泌体以及岩白菜素和牡荆素的组合相比，Exo-Ber + Vit在减少肺纤维化面积、胶原沉积和改善肺功能方面表现出更优异的效果。总之，通过Mlg来源的外泌体共同递送岩白菜素和牡荆素的策略为IPF的治疗提供了一种有前景的新方法。
