Molecular origami in neuroscience: noncanonical DNA structures and functional nucleic acids in neural regulation and disease
5 affiliations
- 1Center for Molecular Design and Biomimetics at the Biodesign Institute, Arizona State University, Tempe, AZ, United States
- 2Department of Physics, Arizona State University, Tempe, AZ, United States
- 3Department of Psychology, University of Michigan, Ann Arbor, MI, United States
- 4Department of Neurology and Neurological Sciences, Stanford Medicine, Stanford University, Stanford, CA, United States
- 5Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
Abstract
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.
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BibTeX
@article{roy2026molecular,
title = {{Molecular origami in neuroscience: noncanonical DNA structures and functional nucleic acids in neural regulation and disease}},
author = {Subhajit Roy and Subhajit Roy and Arpit Kumar Pradhan and Ashwin Kumar Jainarayanan and Ashwin Kumar Jainarayanan},
journal = {Frontiers in Neural Circuits},
year = {2026},
month = oct,
doi = {10.3389/fncir.2026.1893836},
url = {https://doi.org/10.3389/fncir.2026.1893836},
note = {CC BY},
}
RIS
TY - JOUR
TI - Molecular origami in neuroscience: noncanonical DNA structures and functional nucleic acids in neural regulation and disease
AU - Subhajit Roy
AU - Subhajit Roy
AU - Arpit Kumar Pradhan
AU - Ashwin Kumar Jainarayanan
AU - Ashwin Kumar Jainarayanan
PY - 2026
DA - 2026/10/26
JO - Frontiers in Neural Circuits
DO - 10.3389/fncir.2026.1893836
UR - https://doi.org/10.3389/fncir.2026.1893836
AB - 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.
SN - 1662-5110
ER -