Blockade of TGF-β1/Smad3 signaling pathway by Bovine Milk-derived extracellular vesicles ameliorates skin fibrosis in systemic sclerosis mice.

Systemic scleroderma (SSc) causes multi-system fibrosis, damaging the skin, lungs, kidneys, and blood vessels, leading to serious consequences such as organ failure and pulmonary hypertension. Milk-derived extracellular vesicles (Mi-EVs) carry miRNAs and proteins that are antioxidant, promote skin tissue regeneration and reduce inflammation. The TGF-β1/Smad3 pathway drives tissue fibrosis by activating fibroblasts and collagen deposition. This study aimed to investigate the therapeutic effect of Mi-EVs on SSc and the regulation of TGF-β1/Smad3 signaling pathways. In Bleomycin-induced SSc mice, the degree of skin fibrosis was assessed by HE and Masson staining, and collagen and inflammatory levels were tested by ELISA. These findings indicate that Mi-EVs ameliorate skin fibrosis. NIH3T3 mouse embryonic fibroblasts were used to demonstrate that the treatment of Mi-EVs reduced the expression of pro-fibrotic genes. Mi-EVs inhibited TGF-β1-induced phosphorylation of Smad3 in fibroblasts. These findings indicate that Mi-EVs ameliorate systemic sclerosis through the TGF-β1/Smad3 pathway.