Charge-Blind Biosensing: DNA Nanomachine Gating of Ultra-Nanochannels to Detect Neutral Biomarkers

Integrate DNA-based machines such as walkers, strand-displacement switches, and origami hinges as dynamic gates on ultra-thin nanochannels where neutral and charged molecules transport similarly. Detection is achieved via changes in neutral-molecule flux (e.g., small metabolites), amplified by DNA-controlled gating kinetics. This approach exploits the 2–4 nm regime where transport becomes insensitive to charge and diffusivities collapse, directly targeting neutral species that are difficult to detect electrically. DNA machines provide sequence-specific recognition and active gating for amplification and multiplexing. The design reinterprets previously observed unexpected transport behaviors as an advantage rather than a challenge, guided by confined environment nanoarchitectonics and validated by multimodal, physically constrained machine learning imaging and electrostatic force tomography to decouple residual electrostatics from steric and hydration effects. This method addresses the longstanding challenge of neutral-biomarker sensing with real-time, label-free readout and programmability without requiring redox labels or large ionic strength changes. Potential impacts include portable, multiplexed diagnostics for neutral metabolites and drugs and real-time monitoring in complex media where charge-based selectivity fails.

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