Neurotransmitter-Loaded DNA Nanocages as Potential Therapeutics for α-Synuclein-Based Neuropathies in Cells and In Vivo

Parkinson's disease is one of the neuropathies characterized by accumulation of the α-synuclein protein, leading to motor dysfunction. Levodopa is the gold standard treatment; however, in long-term usage, it leads to levodopa-induced dyskinesia (LID). New therapeutic options are need of the hour to treat the α-synuclein-based neuropathies. The role of imbalance of neurotransmitters other than dopamine has been underestimated in α-synuclein-based neuropathies. Here, we explore the role of serotonin, epinephrine, and norepinephrine as a therapeutic moiety. For the efficient in vivo delivery, we use a DNA nanotechnology-based DNA tetrahedron that has shown the potential to cross the biological barriers. In this study, we explore the use of DNA nanodevices, particularly a DNA tetrahedron functionalized with neurotransmitters, as a novel therapeutic approach for MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced Parkinson's disease in a PC12 cellular system. We first establish the effect of these nanodevices on the clearance of the α-synuclein protein in cells. We follow the study by understanding the various cellular processes like ROS, iron accumulation, and lipid peroxidation. We also explore the effect of the neurotransmitter-loaded nanodevices in an in vivo zebrafish model. We show that neurotransmitter-loaded DNA nanocages can potentially clear the MPTP-induced α-synuclein aggregates in cells and in vivo. The findings of these works open up new avenues for use of DNA nanotechnology by functionalizing it with neurotransmitters for future therapeutics in treatment of neurodegenerative diseases such as Parkinson's disease.