<p>Trastuzumab is currently a key targeted drug for HER2-positive gastric cancer (GC), but there are common problems of drug resistance and cardiotoxicity in clinical treatment, resulting in poor therapeutic effects. Exosomes are natural nanocarriers for drug delivery and engineered exosomes have been widely used in translational medicine research. This study is designed to compare the anti-tumor effects and adverse effects between engineered exosomes carrying HER2 siRNA and trastuzumab. The stable cell line of iRGD-293T was constructed by using lentiviruses, and iRGD-293T and 293T cells were transfected with si-HER2 and exosomes were isolated by ultra-centrifugation. Functional experiments were performed to examine the inhibitory effects of iRGD-exo-si-HER2 and trastuzumab on both HER2-positive GC cells and mouse xenograft models. Blood biochemical indexes were used to test the adverse effects, especially cardiotoxicity. The engineered exosomes modified by iRGD peptide showed higher tumor affinity compared to control exosomes in vitro and in vivo. si-HER2 delivered by iRGD-exosomes significantly inhibited the proliferation and promoted apoptosis of HER2-positive GC cells, and iRGD-exo-si-HER2 significantly reduced the expression of HER2 in GC cells in vitro and in vivo, showing similar efficacy as trastuzumab but with lower cardiac side effects. Our data indicated that iRGD-exo-si-HER2 shows good anti-tumor effect both in vivo and in vitro, and has fewer side effects compared with trastuzumab. And this study suggested that engineering exosomes with si-HER2 can serve as novel strategy for the treatment of HER2-positive GC.</p> Graphical Abstract <p></p>