Viscoelastic High‐Molecular‐Weight Hyaluronic Acid Hydrogels Support Rapid Glioblastoma Cell Invasion with Leader–Follower Dynamics

Abstract Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low‐molecular‐weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high‐MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA‐based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader–follower dynamics. Leader cells adopt dendritic morphologies similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress‐relaxing materials to model GBM.