Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily...Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily localizes to myofibroblasts.Exosomes have garnered significant attention as novel drug delivery vehicles,particularly when engineered.However,myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets.In this study,RDYH58,a peptide that targets myofibroblasts,was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes(RDYH58-exo).In vitro and in vivo experiments demonstrated that compared to unmodified exosomes(unm-exo),RDYH58-exo preferentially localized to myofibroblasts.A small interfering RNA targeting FKBP10(siFKBP10)was loaded into exosomes using ultrasonic microfluidics method,and the antifibrotic effects of RDYH58-exo carrying siFKBP10(RDYH58-siFKBP10)were assessed both in vitro and in vivo.The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression,significantly inhibiting fibroblast activation and extracellular matrix deposition,with superior antifibrotic efficacy compared to unmodified exosome vectors(unm-siFKBP10).RNA-seq analysis confirmed the pivotal regulatory role of FKBP10,providing critical evidence for the development of targeted therapeutic strategies.The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.展开更多
基金funded by National Natural Science Foundation of China(Nos.82404552,82273969,and 82473967)Natural Science Foundation of Shandong Province(No.ZR2021MH395,China)+5 种基金Yantai University Doctoral Program(No.SM20B35,China)Development of engineered exosomes for nucleic acid drug delivery in the treatment of pulmonary fibrosis(No.SK22KH114,China)Research on the development of multiple methods to increase exosome production(No.SK22KH304,China)Science Fund of Shandong Laboratory of Advanced Materials and Green Manufacturing at Yantai(No.AMGM2024A07,China)Taishan Scholar Project of Shandong Province(No.tsqn202211112,China)Shandong Laboratory Program(No.SYS202205,China).
文摘Idiopathic pulmonary fibrosis(IPF)is a complex interstitial lung disease in which myofibroblasts are the primary effector cells.FK506-binding protein(FKBP10),a procollagen chaperone,is upregulated in IPF and primarily localizes to myofibroblasts.Exosomes have garnered significant attention as novel drug delivery vehicles,particularly when engineered.However,myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets.In this study,RDYH58,a peptide that targets myofibroblasts,was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes(RDYH58-exo).In vitro and in vivo experiments demonstrated that compared to unmodified exosomes(unm-exo),RDYH58-exo preferentially localized to myofibroblasts.A small interfering RNA targeting FKBP10(siFKBP10)was loaded into exosomes using ultrasonic microfluidics method,and the antifibrotic effects of RDYH58-exo carrying siFKBP10(RDYH58-siFKBP10)were assessed both in vitro and in vivo.The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression,significantly inhibiting fibroblast activation and extracellular matrix deposition,with superior antifibrotic efficacy compared to unmodified exosome vectors(unm-siFKBP10).RNA-seq analysis confirmed the pivotal regulatory role of FKBP10,providing critical evidence for the development of targeted therapeutic strategies.The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.
