Pulmonary‐Targeted Nanoparticles Interrupt the Malignant Mechanical and Biochemical Signaling Crosstalk for Idiopathic Pulmonary Fibrosis Therapy

Idiopathic pulmonary fibrosis (IPF) progression is driven by TGF‐β induced biochemical signals and mechanical signals from increased ECM stiffness. Pulmonary‐targeted VB‐RT NPs not only eliminate excessive ROS and penetrate the dense ECM collagen barrier via NO release, but also simultaneously interrupt the persistent malignant between mechanical and biochemical signaling crosstalk, significantly enhancing therapeutic efficacy in IPF treatment. Abstract Idiopathic pulmonary fibrosis (IPF) involves transforming growth factor‐beta, a key factor that drives biochemical signaling pathways, inducing cellular transdifferentiation and excessive extracellular matrix (ECM) deposition. Increased ECM stiffness alters the mechanical microenvironment of the lung, exacerbating pulmonary dysfunction through mechanical signaling transduction. Here, persistent malignant mechanical and biochemical signaling crosstalk in IPF is demonstrated that drives the relentless progression of the disease. Therefore, inhalable lung‐targeted lipid nanoparticles (VB‐RT NPs) are developed for co‐delivering verteporfin and berbamine to effectively treat IPF by interrupting pulmonary mechanical‐biochemical signaling malignant crosstalk. Specifically, VB‐RT NPs are modified with tannic acid to scavenge reactive oxygen species and enhance lung targeting, and with L‐arginine to penetrate dense ECM and reach deeper lung regions. After being inhaled in a bleomycin model, VB‐RT NPs inhibited fibroblast activation and promoted the transition of endothelial cell (EC)‐like myofibroblasts to ECs, reducing endothelial‐to‐mesenchymal transition and fibrotic progression. Additionally, VB‐RT NPs blocked the nuclear translocation of the mechanotransducers Yes‐associated protein, interrupting fibrosis‐related mechanotransduction pathways. The results demonstrate that VB‐RT NPs effectively reversed dysregulated mechanical‐biochemical signaling crosstalk in fibrotic lungs and halted fibrosis progression, offering a promising therapeutic approach for IPF. Idiopathic pulmonary fibrosis (IPF) progression is driven by TGF-β induced biochemical signals and mechanical signals from increased ECM stiffness. Pulmonary-targeted VB-RT NPs not only eliminate excessive ROS and penetrate the dense ECM collagen barrier via NO release, but also simultaneously interrupt the persistent malignant between mechanical and biochemical signaling crosstalk, significantly enhancing therapeutic efficacy in IPF treatment. Abstract Idiopathic pulmonary fibrosis (IPF) involves transforming growth factor-beta, a key factor that drives biochemical signaling pathways, inducing cellular transdifferentiation and excessive extracellular matrix (ECM) deposition. Increased ECM stiffness alters the mechanical microenvironment of the lung, exacerbating pulmonary dysfunction through mechanical signaling transduction. Here, persistent malignant mechanical and biochemical signaling crosstalk in IPF is demonstrated that drives the relentless progression of the disease. Therefore, inhalable lung-targeted lipid nanoparticles (VB-RT NPs) are developed for co-delivering verteporfin and berbamine to effectively treat IPF by interrupting pulmonary mechanical-biochemical signaling malignant crosstalk. Specifically, VB-RT NPs are modified with tannic acid to scavenge reactive oxygen species and enhance lung targeting, and with L-arginine to penetrate dense ECM and reach deeper lung regions. After being inhaled in a bleomycin model, VB-RT NPs inhibited fibroblast activation and promoted the transition of endothelial cell (EC)-like myofibroblasts to ECs, reducing endothelial-to-mesenchymal transition and fibrotic progression. Additionally, VB-RT NPs blocked the nuclear translocation of the mechanotransducers Yes-associated protein, interrupting fibrosis-related mechanotransduction pathways. The results demonstrate that VB-RT NPs effectively reversed dysregulated mechanical-biochemical signaling crosstalk in fibrotic lungs and halted fibrosis progression, offering a promising therapeutic approach for IPF. Advanced Science, EarlyView.