Polysialic Acid Presentation on Microporous Scaffolds Supports Neural Repair after Ischemic Stroke.

Recovery following ischemic stroke remains limited due to insufficient neural regeneration. Polysialic acid (PSA), a glycan prominently expressed during neural development, modulates neural progenitor cell (NPC) plasticity and migration, but its therapeutic potential in biomaterial-based stroke therapies remains underexplored. In this study, microporous annealed particle (MAP) scaffolds conjugated with PSA (PSA-MAP) were engineered to regulate NPC fate and promote neural tissue regeneration after stroke. PSA-MAP increased the presence of Sox2-positive progenitor cells within infarct and peri-infarct regions and elevated axonal content (NF200) in the lesion, while astrocytic and vascular coverage were not detectably changed at this early stage. In addition, 3D NPC cultures in MAP showed that tethered PSA alters NPC behavior over time, with reduced progenitor marker expression and PSA-dependent shifts in morphology, consistent with progression away from a progenitor state. Together, these data identify a glycan-forward, neuro-first repair route in which PSA-MAP enhances early neural regeneration without requiring concomitant angiogenic expansion, establishing PSA-MAP as a targeted biomaterial approach for endogenous neural repair after ischemic stroke.