Target-Specific Recognition and Standardized Readout: A DNA Nanotransduction Strategy for Nanopore Exosome Sensing toward Clinical Applications

Solid-state nanopores are powerful single-molecule sensing tools, but their reliance on direct translocation requires high analyte concentrations and complicates biochemical specificity. We propose a DNA nanotransduction strategy featuring target-specific molecular recognition and standardized electrical readout, converting complex vesicular information into uniform reporter signals. Glioma-derived exosomes are selectively captured by a dual-aptamer DNA scaffold, which disassembles to release tetrahedral DNA nanostructures (TDNs) as reporter molecules. Since each type of protein on the exosome surface is expressed in multiple copies, each exosome recognition event is translated into multiple translocation signals, shifting from a one-to-one to a one-to-many amplification process. This strategy reduces concentration dependence and relocates specificity to a programmable DNA system, avoiding instability from pore functionalization. Using ∼10 nm silicon nitride nanopores, we demonstrate highly sensitive and specific detection of glioma-derived exosomes and accurate classification in clinical samples. This work establishes a DNA-based nanotransduction system that enhances the versatility of solid-state nanopores for detecting low-abundance biomarkers in complex biological environments, advancing clinical applications.