Background <p>Deoxynivalenol (DON), a mycotoxin produced by Fusarium species, posed significant threats to food safety and human health due to its widespread prevalence and detrimental effects. Upon exposure, the liver, which played a crucial role in detoxifying DON, experienced depleted antioxidant levels and heightened inflammatory responses. Bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-exos) exhibited therapeutic potential by promoting cellular repair and delivering bioactive substances, such as cerium dioxide nanoparticles (CeO₂ NPs), which are recognized for their ability to mitigate oxidative stress and inflammation.</p> Results <p>We successfully loaded BMSC-exos with CeO₂ NPs (BMSC-exos @ CeO₂) using extrusion techniques, verified through electron microscopy and elemental mapping. The resulting BMSC-exos @ CeO₂ displayed low cytotoxicity, boosted antioxidant activity, and reduced inflammation in Hepa 1–6 cells with DON condition. In vivo study, BMSC-exos @ CeO₂ maintained stability for 72&#xa0;h, it also can prevent antioxidant depletion and inhibit liver inflammation under the DON condition. After BMSC-exos @ CeO₂ treatment, multi-omics analyses further highlighted significant changes in metabolic and protein signaling pathways, notably in linoleic and arachidonic acid metabolism. Key pathways about AMPK and JAK1/STAT3 were involved in mitigating liver damage with or without DON.</p> Conclusion <p>Our findings revealed BMSC-exos @ CeO₂ as a promising therapeutic strategy against DON’s toxicity, offering valuable insights into their potential for liver protection.</p> Graphical abstract <p></p>