BACKGROUND: Mesenchymal stem cells (MSCs) possess the capability to mitigate multiorgan failure (MOF) and reduce mortality rates in sepsis. However, their survival is significantly limited due to oxidative stress responses triggered by excessive sepsis inflammation. Previous studies have demonstrated that the paracrine effect of MSCs can be enhanced by cytokine stimuli such as IL-1β, TNF-α, and IFN-γ, a process known as inflammatory licensing. This enhancement, however, may potentially lead to the apoptosis of MSCs. PURPOSE: To investigate the therapeutic effects of Fructus Lycii oligosaccharide (FLO)-nasal mucosa-derived ectodermal MSCs (EMSCs) on septic rats and the underlying mechanisms. STUDY DESIGN AND METHODS: FLO was screened from 21 distinct saccharides derived from traditional Chinese medicine (TCM), utilizing macrophage lipid raft chromatography prepared by our laboratory as the primary screening method.. The comparison of EMSCs primed with/without FLO was assessed through RNA-seq. Cecal ligation and puncture (CLP) surgery was performed in the CLP, EMSCs, and FLO-EMSCs groups (n = 10). The NC group underwent cecal ligation without puncture. The therapeutic effects of EMSCs and FLO-EMSCs on septic rats were evaluated through multiple tests including RT-PCR, western blot, histochemical staining, etc. RESULTS: FLO promoted M2 polarization of macrophages and enhanced the paracrine effect of EMSCs, without inducing apoptosis. Furthermore, FLO promoted GSH synthesis in EMSCs, aiding in the removal of reactive oxygen species (ROS) within these cells. The FLO-treated EMSCs demonstrated enhanced protection against pyroptosis in macrophages, thereby preventing immune paralysis during sepsis. CONCLUSION: This study presents an innovative approach for enhancing the anti-inflammatory properties of MSCs using a TCM-derived oligosaccharide, thereby improving their therapeutic efficacy in sepsis models.