Melatonin-tuned mRNA-loaded lipid nanoparticles enhance NRF2-mediated mesenchymal stem cell therapy for pulmonary fibrosis.

Pulmonary fibrosis is characterized by persistent oxidative stress and excessive extracellular matrix deposition, yet effective therapeutic strategies remain limited. Here, we report a nanoengineering strategy that integrates melatonin and Nrf2 mRNA within lipid nanoparticle (LNPs) to functionally engineer mesenchymal stem cells (MSCs) for redox-targeted antifibrotic therapy. Molecular dynamics simulations and membrane fluidity analyses revealed that melatonin modulates lipid packing in cholesterol-rich LNP membranes, increasing membrane fluidity and facilitating endosomal escape, thereby improving cytosolic mRNA delivery. This membrane-level tuning enabled efficient Nrf2 expression and promoted an antioxidant phenotype in the engineered MSCs. These therapeutic LNP (TN)-engineered MSCs exhibited enhanced cytoprotective and antifibrotic activities in epithelial injury models and in a bleomycin-induced pulmonary fibrosis mouse model. The therapeutic effects were associated with suppression of epithelial-mesenchymal transition and extracellular matrix remodeling. Collectively, this study establishes melatonin-driven membrane modulation as an effective strategy to enhance LNP-mediated mRNA delivery and enable functional engineering of MSCs for redox-targeted regenerative therapy.