As4S4 nanoparticles promote effective terminal erythropoiesis in bone marrow mononuclear cells from patients with myelodysplastic syndromes

Therapeutic choice for refractory anemia arising from ineffective erythropoiesis in myelodysplastic syndromes (MDS) has long remained an unmet demand. In this work, we revealed a novel function of As4S4 nanoparticles with a hydrophilic polymeric coating (ee-As4S4) to promote terminal erythropoiesis in the bone marrow mononuclear cells (BMMNCs) of MDS patients with different subtypes. We showed that ee-As4S4 effectively boosted the mRNA and protein levels of globins, increased the expression of the erythroid differentiation marker CD235a and the proportion of the CD235a+ subpopulation, and reduced the cellular volume of CD235a+ cells. Mechanistic studies demonstrated that ee-As4S4 was able to trigger the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), consequently leading to the increase of globins in mRNA and protein levels, as well as inducing the formation of stress granules (SGs) that caused the segregation and inactivation of eIF4E and inhibited the synthesis of general protein in the BMMNCs. Besides, ee-As4S4 mitigated the oxidative stress in BMMNCs by eliminating intracellular reactive oxygen species. All mechanisms together contributed to the effective differentiation of erythroblasts of early and terminal stages. Therefore, ee-As4S4 hold significant potentials for the treatment of refractory anemia that arises from ineffective erythropoiesis.