Heparan sulfate and glycomimetics: Advances in synthesis and biological applications for post-stroke neurorepair

Heparan sulfate, a structurally diverse glycosaminoglycan that is abundant in the central nervous system (CNS), orchestrates essential processes fundamental to neural plasticity, neurorepair, and neuroprotection. The ability of heparan sulfate to promote regeneration, in stark contrast to the inhibitory effects of chondroitin sulfate and related glycosaminoglycans, has sparked a growing interest in harnessing heparan sulfate and synthetic glycomimetics for post-stroke neurorepair, as well as numerous other neurodegenerative diseases. However, significant gaps persist in our understanding of how sulfation patterns of heparan sulfate can govern functional outcomes, and major barriers remain for clinical translation. Here, we critically review advances in the synthesis and application of heparan sulfate-based glycomimetics, delineate the mechanistic duality of glycosaminoglycans in CNS diseases, and highlight how new preclinical and emerging clinical data are reshaping prospects for bioengineered extracellular matrix therapies. We identify unresolved challenges in delivery, specificity and efficacy, and propose future research directions to bridge these translational divides.