Abstract

Connective tissue growth factor (CTGF) is a key driver in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study presents a groundbreaking supramolecular cryo-shock bone marrow mononuclear cell system for targeted drug delivery in IPF. We incorporated antisense oligonucleotides (ASO) to inhibit CTGF and simultaneously encapsulated nintedanib using the ZMO-E5-NPs carrier for synergistic delivery. The cryo-shock treatment enhances cellular structural integrity and preserves receptor functionality, thereby extending cell viability. By modifying the E5 peptide and conjugating it with DSPE-PEG-MAL, we developed a composite carrier, ZMO-E5-NPs, which demonstrates efficient lung-targeting capability. This system enables rapid nanoparticle capture by fibroblasts through matrix metalloproteinase 2 (MMP2) recognition, ensuring precise delivery of both ASO and nintedanib. In a bleomycin-induced pulmonary fibrosis mouse model, ZMO-E5-NPs-ASO (nintedanib-containing group) significantly attenuated fibrosis progression, improved lung function, and exhibited excellent biocompatibility and safety, highlighting its potential as a novel therapeutic strategy for respiratory diseases.