Research on Therapeutic Strategy of Inhalable Cell Membrane-Coated Nanodelivery Complexes Mediating Nrf2 Pathway for Ameliorating Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is a progressive and fatal chronic lung disease with limited treatment options. Its pathogenesis is closely linked to aberrant activation of oxidative stress. The nuclear factor erythroid 2-related factor 2 (Nrf2), a central regulator of antioxidant responses, represents a promising therapeutic target for IPF. Additionally, M2 macrophage polarization and upregulation of the A_2B Adenosine Receptor (ADORA2B) contribute to fibrosis progression by promoting the secretion of profibrotic mediators such as transforming growth factor-β (TGF-β). Inhalation-mediated drug delivery offers a means to achieve lung-specific targeting, enhancing therapeutic efficacy while reducing systemic side effects. In this study, we developed a biomimetic nanodelivery system (Mul-siRNA@MM) based on M2 macrophage membranes for the codelivery of mulberrin (Mul) and ADORA2B-targeted siRNA. Results indicated that inhalation of Mul-siRNA@MM nanoparticles markedly suppressed Reactive Oxygen Species (ROS) production via activation of the Nrf2 pathway and effectively silenced ADORA2B expression. These actions consequently reduced M2 macrophage infiltration and downstream profibrotic cytokine release, significantly ameliorating bleomycin-induced lung injury and fibrosis in mice. This work not only extends the application of Mul in treating pulmonary fibrosis, but also highlights the potential of inhaled biomimetic nanoparticles as a targeted, safe, and effective strategy for intervening in IPF. It further underscores the therapeutic value of disrupting the crosstalk between oxidative stress and pro-fibrotic signaling pathways.