Key challenges in traumatic brain injury treatment: integrated mechanisms, translational animal models, and advanced...

Aim: To synthesize the mechanistic cascade of secondary injury after traumatic brain injury (TBI) and evaluate emeging drug delivery systems (DSS)in the context of translational therapeutic development.

Methods: This review integrates evidence on secondary injury mechanisms-inclding blood-brain barrier disruption, excitotoxicity, neuroinflammation, oxidative stress, mitochondrial dysfunction, and cerebral edema. Animal models were assessed for reproducibility and biomechanical relevance. Emerging DDS (including liposomes, injectable hydrogels, polymeric nanoparticles, extracellular vesicles, and inorganic nanoformulations) were compared regarding strengths, limitations, safety concerns, manufacturability, and clinical feasibility. Translational barriers and lessons from failed trials were analyzed to propose a mechanism-linked delivery framework.

Results: Secondary injury mechanisms are dynamically interconnected, offering multiple therapeutic targets, but animal model variability limits reproducibility. Each DDS platform demonstrates distinct advantages and limitations in biocompatibility, targeting, and scalability. Despite preclinical promise, clinical translation remains challenging due to poor model fidelity, insufficient pharmacokinetic data, and misalignment between injury mechanisms and delivery strategies.

Conclusion: Links secondary injury mechanisms with rationally designed DDS may improve translation outcomes. Enhancing preclinical riogr and aligning formulation strategies with pathophysiological targets are critical for developmenting effective TBI therapies.