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Stem cell-derived exosomes (SC-Exos) have been shown to protect cells from chemical-induced deoxyribonucleic acid (DNA) damage. However, there has been no systematic comparison of the efficacy of exosomes against different types of DNA damage. Therefore, in this study, we assessed the protective effect of exosomes derived from human embryonic stem cell-induced mesenchymal stem cells (hESC-MSC-Exos) on two types of DNA damage, namely, intra-/inter-strand crosslinks and DNA double-strand breaks induced by cisplatin (Pt) and bleomycin (BLM), respectively, in HeLa cells. The alkaline comet assay demonstrated that hESC-MSC-Exos effectively inhibited Pt- and BLM-induced DNA damage in a dose-dependent manner. When the concentration of hESC-MSC-Exos reaches 2.0 × 106 and 4.0 × 106 particles/mL in Pt- and BLM-treated groups, respectively, there was a significant decrease in tail DNA percentage (Pt: 20.80 ± 1.61 vs 9.40 ± 1.14, p < 0.01; BLM: 21.80 ± 1.31 vs 6.70 ± 0.60, p < 0.01), tail moment (Pt: 10.00 ± 1.21 vs 2.08 ± 0.51, p < 0.01; BLM: 12.00 ± 0.81 vs 2.00 ± 0.21, p < 0.01), and olive tail moment (Pt: 6.01 ± 0.55 vs 2.09 ± 0.25, p < 0.01; BLM: 6.03 ± 0.37 vs 1.53 ± 0.13, p < 0.01). Phospho-histone H2AX (γH2AX) immunofluorescence and western blotting showed an over 50 % decrease in γH2AX expression when the cells were pretreated with hESC-MSC-Exos. As reactive oxygen species (ROS) are important mediators of Pt- and BLM-induced DNA damage, dichloro-dihydro-fluorescein diacetate staining indicated that hESC-MSC-Exos inhibited the increase in intracellular ROS in drug-treated cells. In conclusion, our findings suggest that hESC-MSC-Exos can protect cells from the two types of DNA-damaging drugs and that reduced intracellular ROS is involved in this effect. • hESC-MSC-Exos suppress cisplatin (Pt)- and bleomycin (BLM)- induced DNA damage. • hESC-MSC-Exos inhibit Pt- and BLM- induced decrease of HeLa cell viability. • hESC-MSC-Exos inhibit the generation of intracellular ROS induced by Pt and BLM. [ABSTRACT FROM AUTHOR]