Purpose <p>Creatine plays a key role in human health, improving brain function by improving neuronal activity, memory, and cognitive function. Neurodegenerative diseases and cerebral palsy (CP) are often associated with impaired energy metabolism, oxidative stress, and excitotoxicity, leading to neuronal dysfunction. Creatine supplementation has shown neuroprotective potential, but its efficacy is limited due to poor blood-brain barrier (BBB) permeability and reliance on the creatine transporter (CRT). This study aims to develop and evaluate a glucose dendrimer-conjugated creatine (GD-Creatine) system to facilitate targeted neuronal delivery, overcoming CRT deficiency and enhancing neuroprotection.</p> Methods <p>Creatine was covalently conjugated to the glucose dendrimer via copper-catalyzed azide-alkyne cycloaddition (CuACC) reaction and characterized using ¹H NMR, HPLC, and DLS. The in vitro cellular uptake was assessed using Cy5-GD-Creatine in HT-22 neuronal cells, and the neuroprotective effects of GD-Creatine were evaluated in both glutamate-induced excitotoxicity and oxidative stress models. GD-Creatine uptake was evaluated in the presence of β-guanidinopropionic acid (3GPA), a creatine transporter inhibitor, to determine its transporter-independent cell uptake. The effect of GD-Creatine on NMDA receptor-mediated calcium influx was assessed using the FLIPR assay with Fluo-4 AM dye following NMDA stimulation. Confocal imaging was used to evaluate the brain distribution of GD-Creatine in the CP rabbit model, and behavioral improvements were assessed post-treatment using locomotor and neuroscore analyses.</p> Results <p>GD-Creatine conjugate was synthesized using click chemistry, with a 10 wt% drug payload, with a sustained drug release profile over 14&#xa0;days, under intracellular conditions. The conjugate was efficiently internalized by neurons independent of CRT and exhibited controlled intracellular release, ensuring sustained bioavailability. GD-Creatine significantly reduced glutamate-induced excitotoxicity, oxidative stress, and NMDA receptor-mediated calcium influx, demonstrating its neuroprotective efficacy. In vivo, Cy5-GD-Creatine selectively accumulated in the periventricular white matter and fimbria, key regions affected in CP. Further GD-Creatine–treated CP kits exhibited significant improvements in locomotion, neuromuscular coordination, and reflexive behaviors, suggesting functional recovery.</p> Conclusion <p>GD-Creatine effectively overcomes creatine transporter deficiency, with the dendrimer delivering it into neurons, independent of the CRT mechanism; it enhances intracellular creatine, modulates excitotoxic pathways, and improves neurobehavioral outcomes in CP. This study highlights GD-Creatine as a promising transporter-independent neuroprotective strategy for neurodegenerative diseases and brain injuries, with significant implications for creatine transporter deficiency syndrome. Further investigations are warranted to explore its in vivo efficacy in CRT-deficient models and long-term therapeutic potential.</p> Lay Summary <p>Creatine is essential for brain energy metabolism, but its uptake is impaired in conditions like creatine transporter deficiency and CP. This study introduces GD-Creatine, a novel dendrimer-based delivery system that bypasses the transporter, efficiently enters neurons, and protects against excitotoxicity and oxidative stress. Our findings suggest GD-Creatine as a promising therapy for neurological disorders associated with creatine deficiency.</p>