Inhaled protein nanoparticles achieve synergistic therapy for idiopathic pulmonary fibrosis via reprogramming the ROS/TGF‑β1/SMAD pathway

Idiopathic pulmonary fibrosis (IPF) is a life-threatening lung disorder with unknown etiology and a lack of effective treatment options. Here, we develop inhaled protein nanoparticles (NPs) that deliver agents for the synergistic therapy of IPF with a therapeutic mechanism involving the ROS/TGF-β1/SMAD signaling. The self-assembly NPs (denoted as HbRT) composed of hemoglobin (Hb), resveratrol (RSV), and SB505124 (a potent TGF-β1 receptor inhibitor) are fabricated using a one-pot approach. Upon inhalation, HbRT effectively accumulates in diseased lesions, wherein, RSV eliminates ROS and subsequently inhibits ROS-driven activation of TGF-β1, attenuating oxidative stress and inflammatory responses. In parallel, SB505124 blocking-up TGF-β1/SMAD signaling, thereby inhibiting fibroblast activation and the epithelial-mesenchymal transition (EMT) process. Such a synergism ensures strong therapeutic effects against both bleomycin (BLM)-induced IPF mouse model and human pulmonary fibrosis organoids. This study provides an advanced approach for treating IPF with inhaled protein NPs based on a well-understood mechanism.