Sequential release of N-butylphthalide via multifunctional hydrogel for rapid neuroprotection and sustained neural repair after traumatic brain injury.

Timely neuroprotective therapy in the acute phase, combined with sustained neural repair strategies in the subacute and chronic phases, is crucial for functional recovery following traumatic brain injury (TBI). However, few pharmaceutical interventions currently achieve cross-phasic modulation with a single administration. Thus, developing a drug delivery system with sequential neuroprotective and neural repair capabilities is urgently required. Herein, we fabricated an injectable multifunctional methacrylated alginate hydrogel integrated with cyclodextrin inclusion complexes (to improve the poor solubility of n-butylphthalide, NBP) and a sucrose acetate isobutyrate (SAIB) depot (to extend retention and enable delayed release). A single implantation of this hydrogel into the post-TBI cavity exerted sequential therapeutic effects: it rapidly released NBP to mitigate ferroptosis in the acute phase, subsequently regulated microglial polarization via sustained release, and ultimately enhanced neural plasticity in the late stages in a mouse model. We employed clinical database analysis, mouse transcriptome analysis, and in vivo experiments, which identified ferroptosis as a key driver of the pathophysiological process of TBI. Further network pharmacology, molecular docking, and in vitro experiments demonstrated that NBP attenuated TBI-induced ferroptosis through the GSK-3β-Fyn-Nrf2 pathway. Collectively, our work provides a multi-stage therapeutic platform with controlled NBP release for TBI intervention.