Synergistic Viscoelastic-Oxygenation Strategy in Injectable Granular Hydrogels for Neurovascular Regeneration Post-Ischemic Stroke

Ischemic stroke induces catastrophic neurovascular damage through hypoxia- driven neuronal death and metabolic collapse, characterized by Adenosine Triphosphate (ATP) depletion and mitochondrial dysfunction. In this work, an injectable granular hydrogel platform GUD-HB@PDA is developed, composed of ureidopyrimidinone/dopamine (UPy/DA)-functionalized gelatin (GUD) microspheres and polydopamine-coated hemoglobin (HB@PDA). Attributing to UPy-based quadruple hydrogen bonding and catechol-mediated crosslinking, the hydrogel platform achieves brain-mimetic dynamic viscoelasticity and sustained oxygenation delivery. The import role of viscoelasticity and oxygen supplementation in energy metabolism regulation is confirmed. Notably, it is found that the oxygen supplementation contributes 36–39% ATP increase through alleviates hypoxia, while viscoelastic mechanics contributes 61–64% of ATP increase, dominating the energy regulation through TRPV4-mediated mechanotransduction. This study proves this mechanical bioenergetic regulation synergizing with oxygen-dependent pathways promotes neuronal differentiation and angiogenesis in ischemic-hypoxic environment, through concurrent activation of AMPK-mTOR metabolic pathways and neurogenic differentiation programs. In a photothrombotic stroke model, superior therapeutic efficacy with 5.4-fold neuronal maturation, 1.6-fold vascular infiltration, and 2.8-fold axonal regeneration versus present reports are demonstrated. In summary, focusing on mechanical mismatch and bioenergetic deficits, a unique strategy of viscoelasticity-oxygenation synergy through mechanical cues as fundamental metabolic regulators is established, providing a robust solution for energy-intensive neurovascular regeneration following ischemic stroke.