Key Challenges in Traumatic Brain Injury Treatment: Integrated Mechanisms, Translational Animal Models, and Advanced Drug Delivery Systems

Traumatic brain injury (TBI) remains a leading cause of death and long-term neurological disability worldwide, yet effective disease-modifying therapies are still lacking. This review integrates the mechanistic cascade of secondary injury after TBI, emphasizing dynamic interactions among blood-brain barrier disruption, excitotoxicity, neuroinflammation, oxidative stress, mitochondrial dysfunction, and cerebral edema. We critically evaluate commonly used animal models with attention to reproducibility, biomechanical relevance to human TBI, and key variables that influence outcomes. We further compare emerging drug delivery systems (DDS), including liposomes, injectable hydrogels, polymeric nanoparticles, extracellular vesicles, and inorganic nanoformulations, highlighting their strengths, limitations, safety concerns, manufacturability, and clinical feasibility. Finally, we discuss major translational bottlenecks and lessons from unsuccessful clinical trials and propose a forward-looking framework that links secondary injury mechanisms to delivery strategies. Together, these perspectives aim to guide safer, more effective, and translatable therapeutic development for TBI.