Universal catalytic endothelial lineage nanovesicles for targeting and rescuing ischemic endothelium

Vascular endothelial dysfunction drives major ischemic diseases, yet current nanovesicle therapies lack precise targeting and fail to counteract severe oxidative stress. Here, we engineer a universal, dual-targeting therapeutic platform by functionalizing nanovesicles from induced pluripotent stem cell (iPSC)-derived endothelial cells with antioxidant ceria nanozymes (CeO₂-NMU_iECs). These nanovesicles home to ischemic tissues via the CXCR4/SDF-1 axis and preferentially enter local endothelial cells through homotypic affinity. At the target site, CeO₂-NMU_iECs act synergistically: the nanozymes catalytically neutralize reactive oxygen species, while the vesicles deliver endogenous pro-angiogenic proteins to rescue endothelial function. Systemic administration successfully promoted angiogenesis, mitigated tissue damage, and restored organ function across diverse rodent models of ischemia, including osteonecrosis, skin flap injury, myocardial infarction, and stroke. This nanozyme-arming strategy provides a broadly applicable platform, advancing cell-derived nanovesicles from passive carriers into active microenvironment-modulating therapeutics.