Protein biomarkers derived from plasma exosome have been extensively identified in various diseases. This study aimed to explore the biomarkers at different stages of diabetes retinopathy (DR) progression. Two cohorts, discovery and validation cohorts, were included in this study. The discovery cohort was used for proteomic analysis to screen differentially expressed proteins (DEPs). Hub proteins were identified by Wilcox.test, and their correlation with clinical characteristics were further analyzed. The validation cohort was used for enzyme-linked immunosorbent assay (ELISA) to verify the expression of hub proteins. Receiver operator characteristic (ROC) curve was conducted to evaluate the diagnostic values of hub proteins for DR progression. The correlation with clinical indicators was further analyzed.