Abstract

Cold atmospheric plasma (CAP) has emerged as a promising non-thermal modality in cancer research due to its ability to induce selective cytotoxicity through reactive oxygen and nitrogen species. However, the limited penetration depth and instability of plasma-derived reactive species in complex biological environments remain major obstacles to its therapeutic application. In this study, we investigated whether exosomes derived from CAP-treated cancer cells (CAP-Exo) could serve as functional mediators to extend and amplify the anti-tumor effects of CAP. Using chronic myeloid leukemia K562 cells as a primary model, we demonstrate that CAP treatment induces pronounced oxidative stress, apoptosis, and sustained proliferative suppression. Importantly, exosomes isolated from CAP-treated cells exhibited enhanced anti-proliferative and pro-apoptotic activity in recipient cells compared to exosomes from untreated controls. To assess the broader applicability of this strategy, we further evaluated the effects of CAP and CAP-Exo in multiple solid tumor models, including breast, renal, and hepatocellular carcinoma cells, both in vitro and in vivo . CAP exposure consistently reduced cell viability across solid tumor cell lines, while CAP-Exo retained potent cytotoxic activity against breast cancer cells and significantly suppressed tumor growth in corresponding xenograft models without inducing systemic toxicity. Mechanistically, CAP-induced stress reprogrammed exosomal cargo, enabling the transfer of death-associated molecular signals to recipient tumor cells and thereby promoting apoptosis. Collectively, our findings indicate that CAP-modified exosomes represent a biologically active, cell-free approach that extends the anti-tumor effects of CAP treatment across both hematological malignancies and solid tumors. Rather than replacing existing therapeutic modalities, CAP-Exo may serve as a complementary strategy to enhance CAP-based cancer interventions and overcome current