Double Braking Effects of Nanomedicine on Mitochondrial Permeability Transition Pore for Treating Idiopathic Pulmonary Fibrosis

Abstract Mitochondrial permeability transition pore (mPTP) opening is a key hallmark of injured type II alveolar epithelial cells (AECIIs) in idiopathic pulmonary fibrosis (IPF). Inhibiting mPTP opening in AECIIs is considered a potential IPF treatment. Herein, a “double braking” strategy on mPTP by cyclosporin A (CsA) derived ionizable lipid with 3D structure (3D‐lipid) binding cyclophilin D (CypD) and siRNA downregulating mitochondrial calcium uniporter (MCU) expression is proposed for treating IPF. 3D‐lipid and MCU targeting siRNA (siMCU) are co‐assembled to form stable 3D‐LNP/siMCU nanoparticles (NPs), along with helper lipids. In vitro results demonstrated that these NPs effectively inhibit mPTP opening by 3D‐lipid binding with CypD and siRNA downregulating MCU expression, thereby decreasing damage‐associated molecular patterns (DAMPs) release and suppressing epithelial‐to‐mesenchymal transition (EMT) process in bleomycin‐induced A549 cells. In vivo results revealed that 3D‐LNP/siMCU NPs effectively ameliorated collagen deposition, pro‐fibrotic factors secretion, and fibroblast activation in bleomycin‐induced pulmonary fibrosis (PF) mouse models. Moreover, compared to the commercial MC3‐based formulation, optimized Opt‐MC3/siRNA NPs with incorporating 3D‐lipid 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‐lipid and siMCU will be a promising and potential approach for IPF treatment.