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Haidiya Aierken,1 Bing Jia,1 Bahaerguli Aikeranmu,2 Pazula Aili,3 Weiming Yang,4 Changhao Zhong5 1Respiratory Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 2Department of Respiratory Medicine, Bayingolin Mongolian Autonomous Prefecture People’s Hospital, Urumqi, People’s Republic of China; 3Department of Clinical Medicine, Xinjiang Medical University, Urumqi, People’s Republic of China; 4School of Pharmacy, Kunming Medical University, Kunming, People’s Republic of China; 5State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Changhao Zhong, Email Changhao_Zhong@outlook.comPurpose: Chronic Obstructive Pulmonary Disease (COPD) is a major global health issue characterized by progressive airflow limitation, chronic inflammation, and recurrent infections. Current treatments largely alleviate symptoms but fail to simultaneously address infection-driven and inflammation-driven disease progression. Exosome-based strategies offer a promising alternative, and plant-derived exosomes possess distinct advantages, including low immunogenicity, natural abundance, and simple isolation compared with mammalian exosomes.Methods: We developed a novel dual-functional nanotherapeutic agent by loading ampicillin into exosomes derived from Trigonella foenum-graecum. The resulting ampicillin-loaded exosomes (Exos-AM) harness the natural bioactivity and biocompatibility of plant exosomes to improve drug stability and cellular delivery. The therapeutic efficacy of Exos-AM was evaluated in a murine COPD model induced by lipopolysaccharide (LPS) instillation, cigarette smoke exposure, and P. aeruginosa infection.Results: In vitro, Exos-AM exhibited potent antibacterial activity against S. aureus, E. coli, and P. aeruginosa, while promoting macrophage polarization toward the anti-inflammatory M2 phenotype, thereby alleviating inflammation and attenuating fibrotic responses. Transcriptomic analysis further revealed that Exos-AM modulated macrophage activation through suppression of the NF-κB and MAPK signaling pathways, providing mechanistic insight into its anti-inflammatory effects. In vivo, Exos-AM treatment significantly improved lung histopathology and enhanced bacterial clearance.Conclusion: Our findings underscore the promise of plant-derived exosomes as versatile drug delivery platforms and position Exos-AM as a compelling therapeutic strategy for COPD by concurrently targeting infectious and inflammatory drivers. Keywords: COPD, plant-derived exosomes, macrophage polarization, antibacterial, anti-fibrosis