Journal Article

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

Clarkson, Andrew N., Bhuiyan, Mozammel H., Hinkley, Simon F. R., Smith, Madeleine J.

2026

Overview

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. The extracellular matrix (ECM) and its constituent glycosaminoglycans, particularly heparan sulfate, have emerged as critical regulators of neural functions and recovery in the central nervous system (CNS). This complex and dynamic construct influences synaptic plasticity, cellular communication, neural development and neuroprotection. The architectural complexity of ECM is underpinned by substantial biochemical diversity. Specific sulfation patterns of heparan sulfate modulate molecular signaling pathways influencing neuroprotection as well as neurorepair and regeneration. These findings highlight the important role the ECM plays in cellular regeneration and its relevance as a focus of study. Despite substantial advances, significant gaps persist in understanding the context‐dependent roles that heparan sulfate plays in various neurological diseases. The regulatory mechanisms linking sulfation motifs to functional outcomes remain incompletely described, and large‐scale clinical trials for glycomimetic therapies face considerable barriers, including blood–brain barrier permeability, specificity of action, and long‐term efficacy. Recently, a global consensus called for formal recognition of heparan sulfate as a primary biomarker and therapeutic target in neuronopathic diseases 1 , highlighting ongoing debates over diagnostic tools and endpoints in CNS clinical trials. Recent reviews and research articles also stress that the contribution of ECM to disease progression and neuroregeneration is not sufficiently mapped, citing a lack of data on matrix remodeling, regional specificity, and the interplay with neuroimmune responses 2–4 . This review aims to synthesize current knowledge of heparan sulfate in the CNS, summarize advances in the engineering and application of glycomimetics, and critically discuss the unresolved challenges that restrict clinical utility. By highlighting these knowledge gaps with reference to recent consensus statements and research findings, we outline future directions necessary to realize the therapeutic promise of ECM‐targeted strategies for CNS disorders.

• Publisher: Wiley
• Subject: Review