Engineered MSCs Break Endothelial‐Myofibroblast Crosstalk in Pulmonary Fibrosis: Reconstructing the Vascular Niche

In the progress of pulmonary fibrosis (PF), the normal vascular niche plays a crucial role in alveolar regeneration by secreting angiocrine factors. However, the malignant interaction between myofibroblasts and vascular endothelial cells results in significant loss of pulmonary capillaries in fibroblast foci, which promotes continuous deterioration of fibrosis. Herein, an engineered mesenchymal stem cell (MSC) therapeutic named MSC-MM@LPHN is developed for reconstructing the vascular niche, which is formed by modifying the surface of MSC with ROS-responsive lipid polymeric hybrid nanoparticles encapsulating the metformin and macitentan. Due to the homing ability of MSC, the MSC-MM@LPHN can effectively target lung tissue, then induce myofibroblast dedifferentiation to reduce the secretion of cytokines that cause endothelial cell damage and preventing endothelial cells from turning into a fibrotic phenotype, leading to recovery of the vascular endothelial cells function. Combined with the role of MSC-secreted growth factors promoting angiogenesis, the MSC-MM@LPHN ultimately constructs normal vascular structure in the fibroblast area and reverses bleomycin-induced PF. The findings suggest targeting the cell network in the vascular niche can effectively treat PF, which provides a novel therapeutic strategy for fibrosis-related diseases.