Novel angiogenic metal nanoparticles controlling intracellular gene activation in stem cells

• Previous Cu NPs had high cytotoxicity by fast oxidation and low biodegradation. • Cu-AMNs were significantly improved in oxidation, cytotoxicity, and biodegradation. • Mechanism of intercellular Cu-AMNs on human cells was investigated for the first time. • New concept for metal ion exocytosis and its effect with ADSCs in ischemic disease were covered. Metal and oxide nanoparticles (NPs) are attracting extensive attention in biomedical applications, including bioimaging and drug delivery. However, it is difficult to use these NPs as therapeutic agents for specific cell and tissue treatments because of limitations such as material oxidization and cell toxicity. Herein, we synthesized Cu-based angiogenic metal nanoparticles (Cu-AMNs), using a galvanic replacement reaction of Cu NPs and Au precursor, which stabilized and upregulated intracellular behaviors in human adipose-derived stem cells (hADSCs). Our novel therapeutic Cu-AMNs showed remarkable advantages in cell treatment, such as low mitochondrial damage, reduced ATP consumption, decreased cytotoxicity, mild reactive oxygen species generation with enhanced angiogenic paracrine factor secretion, and improved hypoxia inducible factor-1 alpha (HIF-1α) expression. Through the improved expression of HIF-1α, vascular endothelial growth factor (VEGF) secretion was prolonged for 3 days, even in re-attached hADSCs. In addition, Cu-AMNs improved other angiogenic factors and the amount of exocytosed Cu from hADSCs, resulting in strong development of tubular formation by human umbilical vein endothelial cells in vitro. Finally, transplantation of Cu-AMN-treated hADSCs in mice led to a significant in vivo increase in angiogenesis and blood perfusion in a mouse hindlimb ischemia model compared with conventional hADSC therapy.