Neutrophil membrane engineered human umbilical cord MSC-derived sEVs enhance anti-tumor efficacy for gastric cancer via delivering pentraxin 3.

Gastric cancer poses a significant global health challenge, promoting ongoing updates and exploration of treatment strategies. In this study, we proposed the naïve human umbilical cord mesenchymal stem cell derived small extracellular vesicles (hucMSC-sEVs) effectively inhibit gastric cancer proliferation and migration, presenting a promising bioactive agent for gastric cancer therapy. To address the issues of shortage in circulation time, limited targeting efficiency, suboptimal therapeutic outcomes associated with hucMSC-sEVs, we engineered a membrane fusion between hucMSC-sEVs with human neutrophil membrane, creating Neu/MSC-sEVs. This modification enhanced tumor cell targeting, reduced clearance by the mononuclear macrophage system, prolonged circulation time, and improved therapeutic efficacy. Furthermore, inhibiting the tumor suppressor protein pentraxin 3 (PTX3) in hucMSC-sEVs attenuated their anti-tumor effects, indicating that enrichment with PTX3 enhances the tumor-inhibiting potential of hucMSC-sEVs. Overall, our findings shed light on the mechanism by which hucMSC-sEVs exert their therapeutic effects on gastric cancer and underscore the importance of vesicle modification in enhancing targeting precision and therapeutic outcomes. These findings provide new insights for clinical application of modified vesicles in cancer treatment.