Given the paucity of effective treatments for idiopathic pulmonary fibrosis (IPF), efforts should be made to test and to better characterize new anti-fibrotic drug candidates. The recent development of RNA-targeted therapies using chemically modified oligonucleotide (ASOs) therapeutics show promising clinical outcomes in the treatment of several diseases. This approach is relevant for undruggable targets including non-coding RNAs. Our recent data have highlighted the importance of a family of ncRNAs as key specific regulators of the TGF-? pathway and myofibroblast (MYFs) activation during the pathogenesis of fibroproliferative disorders including IPF. Targeting these ncRNAs using ASO-based therapeutics appears as an attractive therapeutic option and preclinical studies have shown encouraging data. However, these approaches need further developments for translation to the clinic. Our main objective is to optimize the delivery of therapeutic ASOs and address their specificity in mice models of lung fibrosis. Non-invasive imaging will provide unique data on the biodistribution of ASO, as well as on the peak of therapeutic efficacy. Single-cell pharmacogenomics approaches will then be used to evaluate the efficacy and specificity of our drug candidates, providing more specific insights into their mechanism of action and off-target effects in the different cell populations of the fibrotic lung. Finally, as a first proof-of-concept to validate this ASO-based drug in a human context, the best ASO formulation will be evaluated in IPF-derived primary lung fibroblasts using various approaches including single-cell transcriptomics to capture the effect of the drug on the plasticity of these mesenchymal cells. Our project will improve the current knowledge on ASO delivery and safety but should also decipher ncRNA-associated regulatory circuits during MYF differentiation / de-differentiation and their potential interactions with developmental pathways (?-catenin, TGF-? / SMAD, FGFs) reactivated in IPF.