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Inhibiting mPTP opening in AECIIs is considered a potential IPF treatment. Herein, a \u201cdouble braking\u201d strategy on mPTP by cyclosporin A (CsA) derived ionizable lipid with 3D structure (3D\u2010lipid) binding cyclophilin D (CypD) and siRNA downregulating mitochondrial calcium uniporter (MCU) expression is proposed for treating IPF. 3D\u2010lipid and MCU targeting siRNA (siMCU) are co\u2010assembled to form stable 3D\u2010LNP\/siMCU nanoparticles (NPs), along with helper lipids. In vitro results demonstrated that these NPs effectively inhibit mPTP opening by 3D\u2010lipid binding with CypD and siRNA downregulating MCU expression, thereby decreasing damage\u2010associated molecular patterns (DAMPs) release and suppressing epithelial\u2010to\u2010mesenchymal transition (EMT) process in bleomycin\u2010induced A549 cells. In vivo results revealed that 3D\u2010LNP\/siMCU NPs effectively ameliorated collagen deposition, pro\u2010fibrotic factors secretion, and fibroblast activation in bleomycin\u2010induced pulmonary fibrosis (PF) mouse models. Moreover, compared to the commercial MC3\u2010based formulation, optimized Opt\u2010MC3\/siRNA NPs with incorporating 3D\u2010lipid as the fifth component, showed superior therapeutic efficacy against PF due to their enhanced stability and higher gene silencing efficiency. Overall, the nanomedicine containing 3D\u2010lipid and siMCU will be a promising and potential approach for IPF treatment.<\/jats:p>","DOI":"10.1002\/advs.202405406","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T12:01:55Z","timestamp":1730289715000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Double Braking Effects of Nanomedicine on Mitochondrial Permeability Transition Pore for Treating Idiopathic Pulmonary Fibrosis"],"prefix":"10.1002","volume":"11","author":[{"given":"An","family":"Lu","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 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