Zhu Yuehong, Guo Yaoyang, Dong Ziyi, Zhang Mingqing, Liu Hui, Wen Xinyi, Pang Wenwen, Zhang Xipeng, Jiang Zhansheng, Chen Chong, Hao Jie, Gao Ming, Zhang Haiyang
Tianjin Institute of Coloproctology, Tianjin Union Medical Center, Tianjin Key Laboratory of General Surgery in Construction, The First Affiliated Hospital of Nankai University, Tianjin Medical University Cancer Institute and Hospital, Tianjin Cancer Hospital Airport Hospital, Tianjin, 300121, China.
Invest New Drugs. 2025 Jul 24. doi: 10.1007/s10637-025-01558-z.
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.
曲妥珠单抗目前是HER2阳性胃癌（GC）的关键靶向药物，但临床治疗中存在耐药性和心脏毒性等常见问题，导致治疗效果不佳。外泌体是天然的药物递送纳米载体，工程化外泌体已广泛应用于转化医学研究。本研究旨在比较携带HER2 siRNA的工程化外泌体与曲妥珠单抗的抗肿瘤作用和不良反应。利用慢病毒构建iRGD-293T稳定细胞系，将si-HER2转染至iRGD-293T和293T细胞，通过超速离心分离外泌体。进行功能实验以检测iRGD-exo-si-HER2和曲妥珠单抗对HER2阳性GC细胞和小鼠异种移植模型的抑制作用。采用血液生化指标检测不良反应，尤其是心脏毒性。与对照外泌体相比，经iRGD肽修饰的工程化外泌体在体外和体内均表现出更高的肿瘤亲和力。iRGD外泌体递送的si-HER2显著抑制HER2阳性GC细胞增殖并促进其凋亡，iRGD-exo-si-HER2在体外和体内均显著降低GC细胞中HER2的表达，显示出与曲妥珠单抗相似的疗效，但心脏副作用更低。我们的数据表明，iRGD-exo-si-HER2在体内和体外均显示出良好的抗肿瘤作用，且与曲妥珠单抗相比副作用更少。本研究表明，用si-HER2工程化外泌体可作为治疗HER2阳性GC的新策略。
