A pleiotropic single-molecule, sustained-release regenerative scaffold enables coordinated repair after ischemic...

Ischemic stroke induces acute oxidative damage followed by prolonged inflammation and incomplete tissue reconstruction, creating a need for local therapies that provide sustained neuroprotection and repair support. Here, an injectable hybrid scaffold is developed that integrates a brain-compliant hydrogel with short electrospun nanofibers for sustained local delivery of morroniside (MOR), a pleiotropic small molecule with antioxidant, anti-inflammatory and pro-regenerative activities. The hydrogel provides early MOR release to mitigate acute injury, while the nanofibers enable sustained delivery together with extracellular-matrix-mimetic cues that support angiogenesis, neurogenesis, and axonal remodeling. In vitro, MOR enhanced endothelial and neuronal survival and promoted their migration and lineage-specific differentiation under ischemic conditions. In a rat cortical stroke model, MOR-loaded scaffolds significantly improved motor recovery, reduced infarct volume, enhanced vascularization, suppressed glial scarring, and facilitated axonal regeneration. Transcriptomic analysis revealed broad microenvironmental reprogramming, including suppression of inflammatory pathways and enrichment of PI3K-AKT-related repair signaling with increased p-PI3K and p-AKT immunofluorescence. These results demonstrate that coupling a structurally engineered scaffold with a small molecule supports multiple repair-associated responses following ischemic stroke and offers a translational strategy for repairing ischemic brain injury.