An antiswelling biodegradable hydrogel reshapes electro-microenvironment to drive endogenous neuroregeneration after brain defect

Bioactive matrix filling is a promising strategy for treating acute traumatic brain injury (TBI)-related substantial brain defects, requiring a dual-functional matrix that resists swelling and remodels microenvironments for endogenous regeneration. Herein, we design an antiswelling, biodegradable adhesive hydrogel through supramolecular self-assembly of two Food and Drug Administration-approved drugs (lipoic acid and metformin) via multi-hydrogen bonding with precise regulation of solution pH. This hydrogel matrix recapitulates critical native brain tissue characteristics, including mechanical and electrical compatibility. During degradation, released lipoic acid remodels the injury site into a proregenerative niche, while metformin promotes spontaneous recruitment of endogenous neural stem cells (NSCs) to defect area. Integrated with a flexible cortical electrode and exogenous electrical stimulation, this system further directs NSC differentiation into functional neurons. In a substantial brain defect rat model, this strategy achieves a 14.8-fold increase in NSC recruitment and an 11.3-fold enhancement in neuronal differentiation, leading to a 78% reduction in tissue defect volume and notable functional recovery. This work establishes a therapeutic paradigm for endogenous repair after TBI.