Background <p>Diabetic vasculopathy(DV) marks the beginning of the progression from diabetes to myocardial infarction(MI). However, the core genes associated with this disease progression remain unclear, and effective intervention measures are also relatively scarce. This study aims to identify the core genes related to the progression of DV to MI and to evaluate the potential of Ophiopogon-japonicus-derived plant exosomes in blocking this process.</p> Methods <p>Core targets closely associated with the progression of DV to MI were identified through a dual-disease transcriptome analysis from multidimensional aspects including immune infiltration, senescence, and PANoptosis. Subsequently, we isolated plant exosomes derived from Ophiopogon-japonicus(PEDOs) and characterized by electron microscopic imaging and NTA. Further, we evaluated the potential of PEDOs in ameliorating vascular endothelial cell dysfunction under hyperglycemic conditions through flow cytometry, telomerase activity assays, wound healing assays, tube formation assays, western blot, and fluorescence imaging analysis.</p> Results <p>Our findings demonstrated that LIMA1, IL1β, TNF-α, and DKK1 served as the core targets involved in the progression from DV to MI. PEDOs significantly inhibited the expression of these core genes under high-glucose conditions and suppressed the apoptosis of vascular endothelial cells. More importantly, PEDOs significantly promoted angiogenesis by relieving the inhibition of Wnt/β-Catenin signaling by DKK1, and regulated cholesterol metabolism by inhibiting LIMA1 to reduce the uptake of Ox-LDL. However, PEDOs exhibited no significant effect on telomerase activity.</p> Conclusion <p>LIMA1, IL1β, TNF-α, and DKK1 serve as the core targets involved in the progression from DV to MI. PEDOs significantly improve the functional status of vascular endothelial cells under hyperglycemic conditions, representing a promising strategy to prevent the progression of DV to MI.</p> Graphical Abstract <p></p>