Self-assembly of hydrogels for mechanical support and drug delivery has been extensively researched in traumatic brain injury (TBI), where treatment options are limited. The chief challenge is that most self-assembled hydrogels rely on high molecular carriers or the incorporation of exogenous inactive substances as mediators. It is difficult for these drug delivery systems to achieve clinical translation due to concerns regarding biological safety. Here we report a small molecule hydrogel (GBR-gel) loading small molecule drugs (glycyrrhizic acid, berberine, and rhein) that originated from popular Chinese medicines without additional drug loading or inactive components under physiological conditions. In the long run, GBR-gel possesses several advantages, including ease of preparation, cost-effectiveness, and high biocompatibility. As a proof-of-concept, GBR-gel allows for prompt administration at the site of brain injury to exert potent pharmacodynamic effects. Further single-cell RNA sequencing and experimental validation indicated that GBR-gel can effectively rescue the suppressed glutamatergic synapse pathway after TBI, thereby attenuating inflammatory responses and neural impairments. Our work provides an alternative strategy for timely intervention of TBI.
