DNA Origami Hinge Biosensor for Multiplex Nucleic Acid Detection
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Solution Overview
Problem
Current methods for detecting cancer-associated nucleic acids, such as ctDNA and miRNAs, are complex, time-consuming, and expensive, and struggle to differentiate between nucleic acids with minor sequence differences, limiting their use in efficient, point-of-care diagnostics.
Innovation Solution
A DNA origami biosensor is developed with multiple detection sites and hinges, capable of simultaneously detecting different target oligonucleotides through conformational changes induced by hybridization, utilizing FRET or quenching mechanisms to generate a fluorescence signal.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional detection methods (qRT-PCR, NGS, microarray) are used, then detection sensitivity is improved, but device complexity and cost increase significantly
Solution Approach 1:
The detection system is segmented into modular DNA origami units, each containing specific detection elements (toehold domains, fastening domains, fluorophores). These modular segments can be independently designed and assembled, reducing overall system complexity while maintaining high detection sensitivity through standardized interfaces and scalable architecture.
Solution Approach 2:
DNA origami structures serve as intermediary elements that bridge the gap between simple hybridization events and complex detection signals. The origami scaffolds mediate the conversion of molecular binding events into amplified optical signals through precisely positioned fluorophore networks, eliminating the need for complex instrumentation while preserving sensitivity.
2Speed
If direct oligonucleotide hybridization is used, then detection speed is improved, but ability to discriminate single point mutations deteriorates
Solution Approach 1:
The detection system employs dynamic toehold-mediated strand displacement mechanisms that amplify small sequence differences into large conformational changes. The dynamic nature of the strand displacement reactions allows kinetic discrimination of single point mutations while maintaining rapid detection speeds, as the toehold domains provide asymmetric binding that enhances specificity without sacrificing speed.
Solution Approach 2:
The system changes multiple parameters simultaneously - using toehold domain length, fastening domain composition, and fluorophore positioning - to optimize both detection speed and mutation discrimination. By adjusting these parameters, the system achieves high-speed detection while maintaining the ability to distinguish single base differences through cumulative effects on binding kinetics and signal intensity.
3Productivity
If multiple detection sites are integrated into single DNA origami structure, then productivity is improved, but manufacturing precision requirements increase
Solution Approach 1:
The DNA origami design employs universal fastening domain sequences and standardized hinge mechanisms that can be repeatedly implemented across multiple detection sites. This universality allows identical structural modules to be assembled in different configurations and orientations, reducing manufacturing precision requirements through modular replication rather than custom design of each detection site.
Solution Approach 2:
Multiple detection sites are nested within the hierarchical structure of the DNA origami scaffold, with detection elements organized in nested layers. This nesting allows precise positioning to be achieved through cumulative geometric constraints at each hierarchical level, reducing the precision burden on any single manufacturing step while enabling high-throughput multiplexed detection.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The biosensor achieves high sensitivity and specificity in detecting multiple nucleic acids, facilitating rapid and cost-effective diagnostics for cancer biomarkers.
Implementation Method 1
This precise arrangement of multiple fluorophores can be used to create Förster resonance energy transfer (FRET) and/or quenching networks. These FRET-based DNA photonic networks are especially relevant for multiplex detection applications.
Implementation Method 2
In case of optical detection, DNA origami structures can be functionalized with fluorophores. The measurable signal can be detected by optical and electrochemical techniques.
Implementation Method 3
This precise arrangement of multiple fluorophores can be used to create Förster resonance energy transfer (FRET) and/or quenching networks.
Data Source
Figure 1a~1f
Figure 2a~2d
Figure 3a~3b
AI summary
The invention relates to a DNA origami biosensor capable of detecting at least two different target oligonucleotides at the same time, said biosensor comprising at least one DNA origami hinge and at least two detection sites, wherein each detection site comprises a signal emitting array, at least one lock and at least one movable section, wherein the movable sections of the detection sites are connected to each other or to a common DNA origami structure via the at least one hinge.