Exosome-mediated Induction of Apoptosis in Cisplatin-treated GastricCancer Cells as a Strategy to Mitigate Side Effects

Background: Gastric cancer is the third most lethal malignancy worldwide. While cisplatin has shown remarkable efficacy at a low cost, it is also associated with severe side effects. Exosomes play a key role in mediating the bystander effect of radiation and have the capacity to deliver apoptosis signals for targeted destruction of tumor cell. Howev-er, there remains a paucity of research on exosome-mediated bystander effects in the context of chemotherapeutic drugs. Objective: This study aims to investigate the ability of cisplatin-induced exosomes to deliver apoptosis signals to gastric cancer cells, with the aim of mitigating the adverse effects asso-ciated with chemotherapy. Methods: Differential ultracentrifugation was used to isolate apoptotic exosomes secreted by cisplatin-induced gastric cancer MKN-28 cells. Characterization and identification of these exosomes were performed by transmission electron microscopy, particle size analyzer, flow cytometry, and Western blotting. The transduction efficiency of the exosomes was con-firmed through immunefluorescence. The effects of apoptotic exosomes on the proliferation, apoptosis, migration, cycle, senescence, and tumor formation of MKN-28 cells in vitro and in vivo were investigated by live cell workstation, flow cytometry, HE staining, and tumor-igenicity assays. Results: Cisplatin-induced apoptotic exosomes, termed DDP-EXO, exhibited a significantly enhanced inhibitory effect on the proliferation of MKN-28 cells compared to gastric epithe-lial GES-1 cells. Moreover, DDP-EXO was able to deliver apoptotic signals to MKN-28 cells, leading to an increase in the apoptotic population in recipient cells, possibly through the involvement of Caspase-9. Furthermore, DDP-EXO showed limited impacts on cell mi-gration, cell cycle, or cell senescence. In vivo, DDP-EXO effectively suppressed tumorigen-esis in a subcutaneous tumor model without causing detectable pathological changes in main organs and blood samples, suggesting a favorable safety profile. result: Cisplatin-induced apoptotic exosomes, termed DDP-EXO, exhibited a significantly enhanced inhibitory effect on the proliferation of MKN-28 cells compared to gastric epithelial GES-1 cells. Moreover, DDP-EXO was able to deliver apoptotic signals to MKN-28 cells, leading to an increase in the apoptotic population in recipient cells, possibly through the involvement of Caspase-9. Furthermore, DDP-EXO showed limited impacts on cell migration, cell cycle, or cell senescence. In vivo, DDP-EXO effectively suppressed tumorigenesis in a subcutaneous tumor model without causing detectable pathological changes in main organs and blood samples, suggesting a favorable safety profile. Conclusion: In summary, this study provides new perspectives on the potential application of exosomes as an innovative therapeutic approach for gastric cancer.