Abstract

Abstrct Traumatic brain injury (TBI) causes acute neuronal and vascular damage accompanied by intense neuroinflammation, yet current surgical and pharmacological interventions yield limited long-term benefits. Embryonic stem cell-derived small extracellular vesicles (ESC-sEV) carry potent pro-repair signals but suffer from poor brain targeting and rapid clearance in the acute inflammatory window. To address these critical limitations, we engineered an injectable ESC-sEV–glycyrrhizic acid (GA) co-assembled hydrogel (EG-gel) in which sEVs act as a functional gel factor interpenetrating GA nanoscaffolds. GA molecules were self-assembled into nanoscaffolds via hydrogen bonding, with polar head groups coordinating to sEV membranes while hydrophobic cores insert into lipid bilayers, yielding a robust, hierarchical matrix. EG-gel exhibited brain-compatible mechanical properties, rapid self-healing, shear-thinning injectability, and strong tissue adhesion, which collectively enhance local sEV accumulation at the lesion site. In a mouse TBI model, the EG-gel showed superior neuroprotective effects and functional recovery outcomes compared with the GA-gel. Transcriptomics combined with experimental validation confirmed a spatiotemporal synergistic mechanism: GA mediated early inflammatory suppression and immune microenvironment stabilization, while co-assembled sEVs drove angiogenesis and neuronal repair. Therefore, the EG-gel played a synergistic role in establishing a sequential “first anti-inflammatory, then vaso-neural regeneration” microenvironment, thereby promoting neuroprotection after TBI. This work highlights the EG-gel as an up-and-coming candidate for translational therapy in TBI.