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Stem cell transplantation is a promising therapeutic strategy for myocardial infarction. However, transplanted cells face low survival rates due to oxidative stress and the inflammatory microenvironment in ischemic heart tissue. Melatonin has been used as a powerful endogenous antioxidant to protect cells from oxidative injury. However, melatonin cannot play a long‐lasting effect against the hostile microenvironment. Nano drug delivery carriers have the ability to protect the loaded drug from degradation in physiological environments in a controlled manner, which results in longer effects and decreased side effects. Therefore, we constructed poly(lactide‐co‐glycolide)‐monomethoxy‐poly‐(polyethylene glycol) (PLGA‐mPEG) nanoparticles to encapsulate melatonin. We tested whether the protective effect of melatonin encapsulated by PLGA‐mPEG nanoparticles (melatonin nanoparticles [Mel‐NPs]) on adipose‐derived mesenchymal stem cells (ADSCs) was enhanced compared to that of free melatonin both in vitro and in vivo. In the in vitro study, we found that Mel‐NPs reduced formation of the p53‐ cyclophilin D complex, prevented mitochondrial permeability transition pores from opening, and rescued ADSCs from hypoxia/reoxygenation injury. Moreover, Mel‐NPs can achieve higher ADSC survival rates than free melatonin in rat myocardial infarction areas, and the therapeutic effects of ADSCs pretreated with Mel‐NPs were more apparent. Hence, the combination of Mel‐NPs and stem cell transplantation may be a promising strategy for myocardial infarction therapy. S tem  C ells   2018;36:540–550

stem cells

Poly(Lactide‐Co‐Glycolide)‐Monomethoxy‐Poly‐(Polyethylene Glycol) Nanoparticles Loaded with Melatonin Protect Adipose‐Derived Stem Cells Transplanted in Infarcted Heart Tissue