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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\u2010targeted lipid nanoparticles (VB\u2010RT NPs) are developed for co\u2010delivering verteporfin and berbamine to effectively treat IPF by interrupting pulmonary mechanical\u2010biochemical signaling malignant crosstalk. Specifically, VB\u2010RT NPs are modified with tannic acid to scavenge reactive oxygen species and enhance lung targeting, and with L\u2010arginine to penetrate dense ECM and reach deeper lung regions. After being inhaled in a bleomycin model, VB\u2010RT NPs inhibited fibroblast activation and promoted the transition of endothelial cell (EC)\u2010like myofibroblasts to ECs, reducing endothelial\u2010to\u2010mesenchymal transition and fibrotic progression. Additionally, VB\u2010RT NPs blocked the nuclear translocation of the mechanotransducers Yes\u2010associated protein, interrupting fibrosis\u2010related mechanotransduction pathways. The results demonstrate that VB\u2010RT NPs effectively reversed dysregulated mechanical\u2010biochemical signaling crosstalk in fibrotic lungs and halted fibrosis progression, offering a promising therapeutic approach for IPF.<\/jats:p>","DOI":"10.1002\/advs.202512658","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T11:49:53Z","timestamp":1763380193000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pulmonary\u2010Targeted Nanoparticles Interrupt the Malignant Mechanical and Biochemical Signaling Crosstalk for Idiopathic Pulmonary Fibrosis Therapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Xue\u2010Na","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology and Hypertension Affiliated Hospital of Yanbian University  Yanji 133000 China"},{"name":"College of Pharmacy Yanbian University  Yanji 133000 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