Bergenin and vitexin delivery platform using mouse lung fibroblasts-derived exosomes for bleomycin-induced pulmonary fibrosis therapy

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.