Engineered ZFP36-overexpressing AC16 cell-derived extracellular vesicles attenuate ferroptosis-related endothelial injury and functionalize NiTi vascular interfaces

ZFP36 was selected as an MI-associated candidate for donor-cell engineering. • ZFP36 OE -EV attenuated RSL3-induced ferroptosis-related endothelial injury. • ZFP36 OE -EV showed beneficial biological activity in a mouse MI model. • EV-functionalized NiTi interfaces improved vascular healing after implantation. Myocardial infarction (MI) is associated with persistent myocardial injury and vascular dysfunction despite advances in reperfusion therapy. Delayed endothelial recovery, inflammation, and vascular remodeling remain important challenges during post-MI repair and vascular intervention. Here, we investigated whether extracellular vesicles (EVs) derived from ZFP36-overexpressing AC16 cells could attenuate ferroptosis-related endothelial injury, improve cardiac function after MI, and be integrated into a bioactive NiTi surface for vascular repair. Bioinformatic screening identified ZFP36 as an MI-associated candidate linked to ferroptosis-related processes; increased expression was subsequently observed in the mouse MI model. ZFP36-overexpressing AC16 cells were generated, and the released EVs were designated ZFP36 OE -EV. In RSL3-treated HUVECs, ZFP36 OE -EV improved cell viability, reduced oxidative stress, preserved mitochondrial membrane potential, and partially restored ferroptosis-related molecular changes. In a mouse MI model, intramyocardial delivery of ZFP36 OE -EV improved cardiac function and reduced myocardial fibrosis. To explore the use of the same engineered EV preparation for vascular interface functionalization, ZFP36 OE -EV was immobilized onto a polydopamine/hyaluronic acid (PDA/HA)-modified NiTi surface to generate the NPH@Z-EV coating. The coating supported EV loading and gradual particle release in vitro. Under direct cell–material contact conditions, the NPH@Z-EV coating exhibited endothelial protective activity under ferroptosis-related stress. In a rat femoral artery injury model, the NPH@Z-EV coating supported vascular repair, with improved endothelial recovery, reduced local inflammatory activation, attenuated lipid peroxidation-associated vascular injury, and a VSMC marker pattern consistent with reduced phenotypic switching. These findings support further evaluation of engineered EVs as a strategy for functionalizing NiTi vascular interfaces to improve vascular healing after implantation.