In this study, a quercetin-loaded liposome system modified with collagenase was developed to increase QU penetration in the ECM and improve IPF treatment. Quercetin-loaded long circulation liposome (QU-LP) and quercetin-loaded liposome modified with collagenase type I (QU-CLP) were prepared, followed by characterization of the encapsulation efficiency, particle size, morphology, and in vitro drug release. Their effect on the cytotoxicity of A549 cells was detected by the Cell Counting Kit-8, and the cellular uptake was investigated using cellular fluorescence imaging and flow cytometry. TGF-β1 induced A549 cell model was established to mimic pulmonary fibrosis to explore further the anti-pulmonary fibrosis effect of QU-CLP by CCK8 experiment. QU-CLP significantly improves the solubility and bioavailability of QU by encapsulating it in the internal cavity with a high encapsulation efficiency (EE%) of 92.86 ± 1.03%. Liposomes alleviate the influence of QU on normal A549 cell growth. Enhanced fluorescence intensity was observed in A549 cells treated with coumarin 6-labeled and collagenase-modified nanoliposomes (C6-CLP) after 4 h of incubation on the collagen matrix, confirming that collagenase-loaded liposomes could penetrate the collagen barrier and cells internalized more hydrophobic drug. The mean fluorescence intensity (MFI) of the C6-CLP group was 2.88 times that of the C6-labeled nanoliposomes (C6-LP). Moreover, QU-CLP significantly (**P < 0.01) inhibited the proliferation of A549 cells stimulated by TGF-β1. QU-CLP has excellent potential for delivering QU with enhanced bioavailability, high cellular uptake efficiency, and improved therapeutic efficacy in IPF.