Nebulized delivery of multi-modular stem cell-derived exosomes for the treatment of pulmonary fibrosis

Pulmonary fibrosis (PF) is a terminal pathological manifestation of a group of lung diseases characterized by fibroblast proliferation, excessive extracellular matrix deposition, inflammatory damage, and structural destruction of lung tissue. The lung damage caused by PF is typically irreversible. Current medications and therapies can slow disease progression but fail to fully repair the damaged lung tissue. In this study, we developed a composite nanoparticle system from PNP@Exo using Poly(lactic-co-glycolic) acid (PLGA) as a carrier, which is capable of co-delivering the anti-fibrotic drug nintedanib and coated with polydopamine for adhering human umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSCs-Exo) to synergistically harness their therapeutic effects. In vitro experiments demonstrated that the composite drug-loaded nanoparticles PNP@Exo significantly reduced the expression of inflammatory factors, COL I, and COL-III in bleomycin (BLM) induced A549 cells. Furthermore, administration of PNP@Exo into BLM-induced PF mice via nebulization significantly inhibited the production of extracellular matrix components and improved lung function without inducing systemic toxicity. Additionally, PNP@Exo inhibited the ferroptosis process in both PF cells and mice models. In conclusion, the composite drug-loaded nanoparticles synthesized in this study demonstrated a significant therapeutic efficacy in both PF cells and animal models, providing a novel strategy for the treatment of pulmonary fibrosis.