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BackgroundType 2 diabetes (T2D) is an important risk factor for cardiovascular complications. Endothelial dysfunction is a key factor of vascular complications in T2D. We found that erythrocytes (RBCs) undergo dysfunction in T2D which causes endothelial dysfunction. RBCs contain diverse and abundant non-coding (nc)RNAs, of which the expression and function are unknown. We hypothesize that altered function of RBC-derived ncRNAs induces endothelial dysfunction in T2D.AimTo characterize the function of RBC ncRNAs for endothelial dysfunctionTo elucidate how RBC ncRNAs transmit signal to endothelium in T2DTo explore the efficacy of modulating RBC ncRNA as a therapyWork planRBCs are isolated from patients and rodents with T2D as well as healthy controls. ncRNAs are identified via RNA-sequencing and qPCR. ncRNAs are also validated in extracellular vesicles (EVs) released from RBCs. The function of RBC ncRNAs in endothelial dysfunction is examined by co-incubations of RBCs with healthy artery/endothelial cell ex vivo and RBC transfusion rodent model in vivo. The RBC-derived EVs carrying ncRNAs and the signal to the vasculature are determined using molecular, pharmacological and genetic tools. The therapeutic effect of modulating RBC ncRNAs is addressed by determining endothelial function using both patient materials and gene-targeted animals.SignificanceThis study identifies RBC-derived ncRNAs as new disease mechanism and provides new therapy for vascular complication in T2D.