Nitrogen-Doped Graphene Quantum Dots Conjugated to Leucettinib-21 Rescue Differentiating Zebrafish Purkinje Cells by Inhibiting Dyrk1A Kinase.

A major challenge in treating neurological diseases is the transport of compounds across the blood-brain barrier. Herein, we report the synthesis and characterization of nitrogen-doped graphene quantum dots (GQDs) that exhibit high tolerance in zebrafish larvae at high concentrations. In contrast to classical semiconductor quantum dots, vascular microinjection of these fluorescent carbon-based nanomaterials results in rapid tissue distribution and efficient neuronal internalization within the brain, highlighting their potential as nanocarriers for central nervous system delivery. Vascular microinjections of these quantum dots conjugated with the high-affinity Dyrk1A kinase inhibitor Leucettinib-21 (LCTB21) at nanomolar concentrations rescued cell-autonomous dendrite deficiencies in cerebellar Purkinje cells overexpressing human Dyrk1a. LCTB21 concentrations were significantly lower than those of the inhibitor alone. Dyrk1A activity is responsible for neurological defects in Down syndrome and acts as a priming kinase for Alzheimer's disease-associated proteins Tau and APP. Thus, efficient nanodelivery of Dyrk1A inhibitors across the blood-brain barrier improves therapeutic options while minimizing the treatment dose and potential side effects.