Background <p>Traumatic brain injury (TBI) can induce both primary and secondary brain injuries. Hampered by a multitude of constraints, including the complexity of secondary injury pathophysiological mechanisms, the selective permeability of the blood-brain barrier (BBB), and the side effects of therapeutic agents, systemic monotherapy has demonstrated limited efficacy in improving the long-term prognosis of TBI patients. Therefore, there is an urgent need to develop novel therapeutic strategies that can bypass the BBB, avoid systemic complications, and target multiple secondary injury mechanisms simultaneously.</p> Methods <p>An injectable dual-drug-loaded nanohydrogel system was synthesized and its characteristics were evaluated. A mouse controlled cortical impact (CCI) model was established, and the nanohydrogel was locally administered intraoperatively. The neurological prognosis of mice was observed in both acute and chronic phases. Multiple methods, including evans blue assay, magnetic resonance imaging, transmission electron microscopy, western blot, enzyme-linked immunosorbent assay, and immunofluorescence staining, were used to evaluate the cerebral edema, BBB integrity, neuroinflammation, neuronal death/survival, angiogenesis, and neurogenesis after TBI.</p> Results <p>The nanohydrogel hybridizes hemoglobin (Hb) nanoparticles (NPs) with brain-derived neurotrophic factor (BDNF), uses these as the core to synthesize polydopamine (PDA) NPs, and loads dexamethasone (DEX) on their surface. In vitro drug release experiments confirmed that BDNF@Hb-PDA@DEX@gel had a high drug-loading rate and sequential sustained-release characteristics. The hydrogel matrix exhibited hemostatic and antibacterial effects. Both in vitro and in vivo experiments showed that the nanohydrogel could effectively reduce the acute-phase inflammatory response, protect BBB integrity, and alleviate cerebral edema by releasing DEX. In the late stage, it could promote brain tissue repair by releasing BDNF, including angiogenesis, neurogenesis, and neuron survival. The therapeutic efficacy of this dual-drug sequential delivery system was significantly superior to that of DEX monotherapy, and it could improve both acute and chronic neurological functions.</p> Conclusions <p>By virtue of local sequential and sustained release of multiple drugs, the injectable nanohydrogel-based dual-drug delivery system can target multiple secondary injury mechanisms of TBI and exert spatiotemporal therapeutic effects, which provides a new strategy for the effective management of complex secondary brain injury and the improvement of long-term prognosis in TBI.</p>