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Pirfenidone (PFD) shows great antifibrotic potential but is clinically hindered by low bioavailability and gastrointestinal side effects. To address these limitations, this study develops a PFD delivery system (PFD\u2010Exo) using J774A.1 macrophage\u2010derived exosomes. Firstly, PFD is loaded via sonication, then PFD\u2010Exo is characterized using Raman spectral imaging and UV absorption spectroscopy. Finally, in vitro and in vivo silicosis models are established to evaluate its antifibrotic effects. Results show that PFD\u2010Exo outperforms free PFD in inhibiting TGF\u2010\u03b21\u2010induced transdifferentiation of primary lung fibroblasts in vitro. In a mouse model of silicosis, PFD\u2010Exo is found to be accumulated in the lungs following intratracheal administration and significantly ameliorates pulmonary inflammation and fibrosis while minimizing gastrointestinal side effects. Mechanistic studies reveal that PFD\u2010Exo modulates the TGF\u2010\u03b2 signaling pathway by downregulating SMAD3 and upregulating SMAD7 and NOGGIN. In conclusion, this study provides the first evidence of macrophage\u2010derived exosomes as an effective PFD delivery system for silicosis treatment and offers a promising strategy for other refractory pulmonary diseases.<\/jats:p>","DOI":"10.1002\/adhm.202403227","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T08:25:34Z","timestamp":1728462334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Engineering Macrophage\u2010Derived Exosome to Deliver Pirfenidone: A Novel Approach to Combat Silicotic Pulmonary Fibrosis"],"prefix":"10.1002","volume":"14","author":[{"given":"Zhen","family":"Chen","sequence":"first","affiliation":[{"name":"Clinical Medical Research Center for Women and Children Diseases Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao 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