Small extracellular vesicle-integrated by herbal hydrogels for spatiotemporal immunomodulation and neurovascular repair following traumatic brain injury.

Abstract

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.