Antioxidants have potentials to treat hypoxia-mediated oxidative stress related diseases. However, their therapeutic efficacy is restricted due to its poor cellular uptake efficiency and poor cell membrane permeability. To resolve these issues, we prepare the hydroxyethylated chitosan nanoparticles as drug carriers for the delivery of 6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid ... [Show full abstract] (Trolox), which was considered as a model compound. The experiment on cellular uptake and subcellular localization of Trolox-loaded chitosan nanoparticles (Trolox-CSNPs) indicate that Trolox-CSNPs enter the cells via the caveolae-mediated endocytosis pathway and traffic with endosomes. Furthermore, compared with Trolox, Trolox-CSNPs exert a higher protective effect against the hypoxia-mediated oxidative stress. Molecular basis of apoptosis study reveals that Trolox-CSNPs can directly block the mitochondria dependent apoptotic pathway through up-regulation of Bcl-2 expression and inhibit the activation of Bax, Caspase-3 expression. In conclusion, the hydroxyethylated chitosan is a promising drug nanocarrier to deliver antioxidants for the treatment of hypoxia-mediated disease.