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已发表论文
吸入式 TFRC 靶向细胞外囊泡递送 siTGF-β1 通过双重抑制铁死亡和成纤维细胞激活缓解肺纤维化
Authors Liang H, Lang Q, Liang Z, Sun J
Received 16 September 2025
Accepted for publication 23 January 2026
Published 2 February 2026 Volume 2026:21 568106
DOI https://doi.org/10.2147/IJN.S568106
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Lijie Grace Zhang
Huan Liang,1,* Qin Lang,2,3,* Zongan Liang,2 Jian Sun2
1Center of Infectious Diseases, West China Hospital, Sichuan University; West China School of Nursing, Sichuan University, Chengdu, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jian Sun, Email sunjian1981@126.com
Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder marked by excessive extracellular matrix deposition and limited treatment options. Ferroptosis has emerged as a critical driver of epithelial injury and fibrogenesis, while fibroblast activation further accelerates pathological remodeling. The transferrin receptor (TFRC), aberrantly upregulated in both alveolar epithelial cells and fibroblasts during fibrosis, represents a promising target for precision therapy.
Methods: An engineered extracellular vesicle (EV) platform was developed using human umbilical cord mesenchymal stem cell-derived vesicles (HucMSC-EVs). By conjugating a T7 peptide for TFRC targeting and encapsulating small interfering RNA against transforming growth factor-beta 1 (siTGF-β 1) through electroporation, a dual-functional nanocomplex (T7-EV/siTGF-β 1) was generated. Its delivery efficiency, molecular effects, and therapeutic outcomes were systematically evaluated in vitro and in bleomycin-induced pulmonary fibrosis mouse models.
Results: T7-EV/siTGF-β 1 achieved targeted uptake by epithelial cells and fibroblasts, efficiently silencing TGF-β 1 expression. Treatment significantly inhibited iron accumulation, reactive oxygen species (ROS) generation, and lipid peroxidation, thereby suppressing ferroptosis. Concurrently, the nanocomplex reduced myofibroblast activation, collagen deposition, and fibrotic remodeling, ultimately improving lung histopathology and respiratory function. Importantly, aerosolized administration enabled preferential lung accumulation with minimal off-target distribution and excellent biocompatibility.
Conclusion: This study demonstrates that simultaneous inhibition of epithelial ferroptosis and fibroblast activation via TFRC-targeted EV-mediated siRNA delivery effectively mitigates pulmonary fibrosis. T7-EV/siTGF-β 1 thus offers a synergistic and clinically translatable strategy for treating IPF and other fibrotic lung diseases.
Plain Language Summary: Alveolar epithelial ferroptosis promotes fibroblast activation through TGF-β 1 signaling.TFRC is upregulated during early-to-mid fibrosis, enabling stage-specific targeted delivery.T7-modified MSC-derived EVs exhibit enhanced TFRC-mediated targeting and siRNA delivery.T7-EV/siTGF-β 1 suppresses ferroptosis and oxidative stress in bleomycin-injured epithelial cells, and inhibits TGF-β 1-mediated fibroblast activation in vitro and vivo.
Keywords: extracellular vesicles, T7 peptide, TFRC, ferroptosis, pulmonary fibrosis
1Center of Infectious Diseases, West China Hospital, Sichuan University; West China School of Nursing, Sichuan University, Chengdu, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jian Sun, Email sunjian1981@126.com
Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder marked by excessive extracellular matrix deposition and limited treatment options. Ferroptosis has emerged as a critical driver of epithelial injury and fibrogenesis, while fibroblast activation further accelerates pathological remodeling. The transferrin receptor (TFRC), aberrantly upregulated in both alveolar epithelial cells and fibroblasts during fibrosis, represents a promising target for precision therapy.
Methods: An engineered extracellular vesicle (EV) platform was developed using human umbilical cord mesenchymal stem cell-derived vesicles (HucMSC-EVs). By conjugating a T7 peptide for TFRC targeting and encapsulating small interfering RNA against transforming growth factor-beta 1 (siTGF-β 1) through electroporation, a dual-functional nanocomplex (T7-EV/siTGF-β 1) was generated. Its delivery efficiency, molecular effects, and therapeutic outcomes were systematically evaluated in vitro and in bleomycin-induced pulmonary fibrosis mouse models.
Results: T7-EV/siTGF-β 1 achieved targeted uptake by epithelial cells and fibroblasts, efficiently silencing TGF-β 1 expression. Treatment significantly inhibited iron accumulation, reactive oxygen species (ROS) generation, and lipid peroxidation, thereby suppressing ferroptosis. Concurrently, the nanocomplex reduced myofibroblast activation, collagen deposition, and fibrotic remodeling, ultimately improving lung histopathology and respiratory function. Importantly, aerosolized administration enabled preferential lung accumulation with minimal off-target distribution and excellent biocompatibility.
Conclusion: This study demonstrates that simultaneous inhibition of epithelial ferroptosis and fibroblast activation via TFRC-targeted EV-mediated siRNA delivery effectively mitigates pulmonary fibrosis. T7-EV/siTGF-β 1 thus offers a synergistic and clinically translatable strategy for treating IPF and other fibrotic lung diseases.
Plain Language Summary: Alveolar epithelial ferroptosis promotes fibroblast activation through TGF-β 1 signaling.TFRC is upregulated during early-to-mid fibrosis, enabling stage-specific targeted delivery.T7-modified MSC-derived EVs exhibit enhanced TFRC-mediated targeting and siRNA delivery.T7-EV/siTGF-β 1 suppresses ferroptosis and oxidative stress in bleomycin-injured epithelial cells, and inhibits TGF-β 1-mediated fibroblast activation in vitro and vivo.
Keywords: extracellular vesicles, T7 peptide, TFRC, ferroptosis, pulmonary fibrosis