Molecular origami in neuroscience: noncanonical DNA structures and functional nucleic acids in neural regulation and disease

Gliomas are increasingly recognized as network diseases in which aberrant interactions between tumor cells, neurons, and immune populations drive hyperexcitability, seizures, cognitive dysfunction, and disease progression. Simultaneously, advances in structural biology and nucleic acid engineering have revealed DNA to be a dynamic molecular architecture capable of sensing, regulating, and modulating cellular states. In this review, we examine how noncanonical DNA structures and functional nucleic acids including Z-DNA, G-quadruplexes, cruciform structures, aptamers, and DNA origami systems, shape neural regulation and glioma associated circuit pathology. We discuss how activity dependent DNA conformational transitions influence transcriptional programs controlling neurotransmission, ion channel expression, synaptic signaling, metabolism, and inflammatory pathways in glioma cells and peritumoral neural networks. Z-DNA formation appears linked to rapid transcriptional activation and enhancer dynamics, whereas G-quadruplex rich regulatory regions modulate genes associated with excitatory signaling, cellular proliferation, and tumor progression. Cruciform DNA structures additionally interface with genome stability and DNA repair, creating mechanistic entry points for therapeutic intervention. Beyond endogenous DNA architectures, we highlight the emergence of aptamer based diagnostics and therapeutics capable of detecting neurotransmitters, cytokines, and metabolites associated with glioma induced network dysfunction. DNA origami platforms further enable programmable multivalent delivery systems for targeted transport of small molecules, oligonucleotides, CRISPR machinery, and ion-channel modulators across the neurovascular unit and tumor microenvironment. We also explore closed-loop neuromodulatory strategies in which electrophysiological signatures guide state dependent therapeutic actuation through nucleic acid based sensing and delivery systems. Finally, we discuss key translational considerations, including blood brain barrier delivery, nuclease stability, immunogenicity, biodistribution, manufacturing reproducibility, and integration with existing neuro-oncology and anti-seizure therapies. By bridging molecular origami, electrophysiology, and neurotechnology, this review proposes a framework for precision neuromedicine in glioma and broader neurological disease, where programmable nucleic acid architectures are coupled to the dynamic circuit states that drive pathology.