Background: Genetic modulation would be an attractive alternative to enhance stem cell function and/or cell survival. Hepatocyte growth factor (HGF) is a well known growth factor to stimulate angiogenesis and recruit stem cells to ischemic myocardium. In this study, we transferred HGF gene to umbilical cord blood-mesenchymal stem cells (UCB-MSC) by using supermagnetic iron oxide nanoparticles (SPION) with high safety and efficacy to enhance cellular function. Methods and Results: Human HGF gene was cloned into eukaryotic expression vector pcDNA3.1 and SPION were synthesized and coated with polyethylenimine (PEI). DNA binding capacity of SPION was assessed by gel retardation assay. Plasmid DNA was mixed and incubated with SPION for at room temperature with various N/P ratio. After 15 min, the mixture was separated on 0.8% agarose gel to determine the binding of plasmid DNA and SPION. For transfection to UCB-MSCs, the mixture of plasmid DNA and SPION was incubated for 15 min then added to UCB-MSC culture. One day after transfection, cultured media and cells were collected to be analyzed by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. SPION did not show any toxic effect on UCB-MSCs. HGF mRNA and protein released into media were drastically increased after 24 hours transfection. HGF-overexpressed UCB-MSCs were more resistant to oxidative stress than mock vector transfected UCB-MSCs. Conclusion: HGF gene was highly expressed in UCB-MSCs through SPION without cytotoxicity. In conclusion, SPION is an efficient gene transfer vector to UCB-MSC and would be utilized for cell trafficking in stem cell study in animal model.