Nonmonotonic Enhancement of Signal Gain by Outer-Surface Charge in Nanopores: toward Precise Single-Entity Detection.

Nanopore technology is a powerful tool for studying the native structures and properties of single entities. However, it sometimes suffers from insufficient accuracy and a potential false positive rate due to low ionic current signal gain. Herein, we report a methodology whereby the manipulation of nanopore outer-surface (OS) charges enhances the ionic current signal gain, which, in turn, improves detection accuracy in single-entity analysis. The results demonstrate that OS charges enhance the ionic current change value (ΔI) and ionic current change rate (β), two key signals for nanopore single-entity analysis. Both signals exhibit OS charge-dependent optimization thresholds for high accuracy, with ΔI peaking at an OS charge of 1.100 C/m² and β peaking at 0.600 C/m² (computational modeling framework established in this work). This finding provides valuable guidance for developing and designing nanopore sensors for high-accuracy, single-entity detection.