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Vascular endothelial dysfunction is a central pathophysiological mechanism underlying a broad spectrum of metabolic diseases, including type 2 diabetes mellitus, atherosclerosis, obesity, and non-alcoholic fatty liver disease. As a metabolically active interface, the endothelium regulates vascular tone, inflammation, oxidative stress, and nutrient exchange; its impairment contributes to the initiation and progression of these disorders. This review synthesizes current understanding of the molecular mechanisms linking endothelial dysfunction to metabolic disease progression. Particular focus is placed on emerging nanotechnology-based strategies designed to restore endothelial function. These include a diverse array of nanoparticles (NPs)-such as liposomes, polymeric carriers, metallic NPs, and non-metallic inorganic NPs-engineered for endothelial targeting, anti-inflammatory action, angiogenesis modulation, and oxidative stress reduction. Finally, we outline the major challenges facing clinical translation, including endothelial heterogeneity, insufficient cell-specific delivery validation, barriers for emerging biotherapies, and unresolved issues in long-term safety, manufacturability, and regulatory feasibility. Nanomedicine holds significant potential to revolutionize metabolic disease management by enabling precise, endothelium-centered diagnosis and therapy.