Engineering Heparan Sulfate-Guided Peptide Self-Assembly to Restore Endothelial Angiogenesis under Hyperglycemia

Hyperglycemia-induced endothelial dysfunction impairs cytoskeletal plasticity, cell migration, and angiogenesis, contributing to the pathogenesis of diabetic vascular complications. To address this, we engineered a heparan sulfate (HS)-targeting peptide that couples a glycan-binding motif with a self-assembling domain, enabling localized formation of supramolecular nanostructures at the endothelial surface. These assemblies attenuate actomyosin contractility by remodeling cell-matrix interactions, thereby restoring contractile homeostasis, the dynamic equilibrium of intracellular tension and cytoskeletal adaptability, without compromising global cytoskeletal integrity. In vitro, the peptide reverses hyperglycemia-induced cytoskeletal stiffening, enhances endothelial motility, and rescues network formation in Matrigel tube formation assays, without inducing cytotoxicity. Through plasma membrane surface-selective self-assembly, this HS-guided platform offers a localized, biomimetic strategy for correcting mechanical dysfunction in diabetic endothelium and holds translational potential for vascular repair in metabolic diseases.