Neuron‐targeted 2‐deoxyglucose‐dendrimer‐rosiglitazone nanotherapy mitigates neuroinflammation and cognitive deficits in pediatric traumatic brain injury

Traumatic brain injury (TBI) remains a major global health challenge, characterized by high morbidity and mortality rates. Despite advances in neuroscience, the blood–brain barrier (BBB) limits the effectiveness of potential neuroprotective treatments. Recent nanotechnology breakthroughs have led to smart drug delivery systems that can cross the BBB and target injured brain areas. However, achieving the specificity needed to deliver therapies to affected neurons remains a challenge. In previous work, we developed a mixed‐layered dendrimer functionalized with 2‐deoxyglucose (2DG‐D) for selective neuronal drug delivery. In this study, we explore the therapeutic potential of rosiglitazone (Rosi) for pediatric TBI by creating a 2DG‐D‐Rosi nanosystem, where Rosi is conjugated to 2DG‐D to improve its solubility, bioavailability, and targeted delivery to injured neurons. In vitro, 2DG‐D‐Rosi demonstrated high neuronal uptake, sustained drug release, and excellent biocompatibility. It significantly reduced neuronal apoptosis, reactive oxygen species formation, pro‐inflammatory cytokine expression, and caspase activity, outperforming free Rosi. In vivo, using a pediatric TBI mouse model, 2DG‐D‐Rosi improved neuronal targeting, reduced neuroinflammation, and enhanced behavioral outcomes. This research highlights 2DG‐D‐Rosi as a promising nanotherapeutic platform for precise TBI treatment and sets the stage for developing more effective therapies for this challenging condition.