Multifunctional Nanoparticles in Traumatic Brain Injury: From Targeted Imaging and Diagnosis to Innovative Therapeutics.

Traumatic brain injury (TBI) remains a leading cause of morbidity and mortality worldwide, with limited therapeutic progress due to challenges such as impermeability of the blood-brain barrier (BBB) and the multifactorial nature of secondary neurodegeneration. Nanoparticle-based platforms, owing to their tunable physicochemical properties, surface modifiability, and multifunctionality, have emerged as promising tools for both diagnosis and therapy. A wide range of inorganic, organic, and carbon-based nanoparticles has demonstrated improved imaging contrast, enhanced biosensing capabilities, and potential for targeted, real-time diagnostics. On the therapeutic front, nanoparticles have shown the ability to concentrate therapeutic agents at or near injury sites; however, achieving precise delivery remains a major challenge. Indeed, nanoparticle-based therapies are still limited by off-target accumulation in peripheral organs, incomplete BBB penetration, and heterogeneous tissue distribution. Addressing these barriers requires optimizing particle size, surface charge, ligand conjugation, and degradability to improve site-specific targeting and minimize systemic toxicity. In this review, we examine major classes of nanoparticles, including organic, inorganic, carbon-based, and biologically derived nanocarriers, and discuss the key physicochemical properties governing their interactions with the central nervous system. We evaluate their applications in TBI diagnosis, neuroimaging, and therapy, emphasizing the design principles influencing blood-brain barrier penetration, targeting specificity, biodistribution, and clearance. We further assess emerging nanoparticle-based strategies to improve site-specific delivery and mitigate secondary brain injury, and highlight key translational challenges and future clinical directions. Continued research into biodegradable, biomimetic, and environmentally sustainable synthesis methods is essential to advancing nanoparticle design and ensuring their safe and effective integration into the clinical management of TBI.