Mesenchymal stem cell-derived small extracellular vesicles rebalance Th2/Th17 responses and attenuate epithelial remodeling in eosinophilic chronic rhinosinusitis

MSC-sEV attenuate eosinophilic nasal inflammation and mucosal remodeling in vivo. • MSC-sEV restore splenic Th1 and reduce Th17 cells, rebalancing T-helper responses. • MSC-sEV attenuate EMT-like changes and epithelial barrier dysfunction in ECRS. • RNA-seq and immunoblot link MSC-sEV effects to IL-17, TNF and JAK-STAT signaling. • Intranasal MSC-sEV offers a cell-free nanotherapy for refractory ECRS. Eosinophilic chronic rhinosinusitis (ECRS) is a refractory subtype characterized by dominant Th2 inflammation and progressive tissue remodeling, with high postoperative recurrence and limited efficacy of current biological agents. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) represent a promising cell-free nanotherapeutic approach, yet their efficacy in ECRS remains poorly studied. This study investigated the therapeutic efficacy of intranasal MSC-sEV against Th2/Th17 immune dysregulation and mucosal remodeling in a papain-induced ECRS model. Intranasal administration of MSC-sEV during the challenge phase significantly alleviated clinical symptoms and attenuated key pathological features, including epithelial hyperplasia, goblet cell hyperplasia, excessive mucus secretion and mucosal eosinophil infiltration, the latter confirmed by direct eosinophil quantification on H& E -stained sections. Immunohistochemistry showed that MSC-sEV attenuated airway remodeling by downregulating markers such as FXIII-A and CLCA1 while partially restoring E-cadherin levels, indicating attenuation of EMT-like changes. Flow cytometry of splenic lymphocytes revealed that MSC-sEV partially restored the disturbed systemic Th1/Th2/Th17 balance, with a more evident effect on the Th17-associated response, and immunohistochemistry for GATA3, IL-17 A and TNF-α confirmed concordant changes in the nasal mucosa. Transcriptomic analysis showed that these therapeutic effects were associated with downregulation of eosinophil-recruitment chemokines ( Ccl11 , Ccl24 ) and with reduced enrichment of IL-17, TNF and JAK-STAT signaling—corroborated at the protein level by decreased phosphorylation of STAT3 and NF-κB p65 and by RT-qPCR confirmation of nine key transcripts. Collectively, this study identifies MSC-sEV as an effective cell-free strategy that attenuates the development of ECRS by partially restoring immune homeostasis and attenuating epithelial remodeling. Download: Download high-res image (172KB) Download: Download full-size image