The goal of this study was to investigate the mechanism of PLPs-MSNs-AsIV on MIRI. In H/ R-induced H9c2 cells, we found increased cell damage, increased autophagy, and down-regulated phosphorylation of PI3K,AKT, and mTOR. After the addition of AsIV and PLPs-MSNs-AsIV, we observed an increase in the expression of P62 and a decrease in the expression of Beclin1 and LC3, implying a decrease in the level of autophagy, while PI3K/AKT/mTOR was activated and the cell damage was reduced. These findings propose that PLPs-MSNs-AsIV might regulate MIRI through modulation of autophagy via the PI3K/AKT/mTOR pathway, and that PLPs-MSNs-AsIV is superior to AsIV. Finally, rescue experiments further demonstrated that PLPs-MSNs-AsIV controlled autophagy via the PI3K/AKT/mTOR pathwayto protect cardiomyocytes. Our results reveal that PLPs-MSNs-AsIV protects myocyte by inhibiting autophagy through the PI3K/AKT/mTOR pathway and present a novel therapeutic strategy for MIRI.