Ampicillin-Loaded Fenugreek-Derived Exosomes Treat COPD via Anti-Inflammatory, Antibacterial and Anti-Fibrotic Effects

Purpose: 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