Probing Inner-Tip Access-Resistance Modulation by ssDNA in a Nanopipette Using a Single-Molecule Nanomanipulation System

Abstract The transport of flexible polyelectrolytes through nanoscale confinements is fundamental to polymer physics and biophysics, yet direct observation remains challenging. Using a nanopipette-based single-molecule nanomanipulation platform, we controllably translocate long single-stranded DNA (ssDNA) through a solid-state nanopore, enabling real-time tracking of chain dynamics with nanoscale precision. We discover that ssDNA generates a characteristic progressive current decrease with terminal oscillations─absent for rigid double-stranded DNA. Evidence indicates this signal arises from inner-tip access-resistance modulation by the ssDNA coil, with a linear relationship between current blockade and relative escape displacement. Systematic variation of voltage and nanopore geometry reveals electric-field-driven stretching of the ssDNA coil and extended interaction with the inner tip region. This provides a framework for interpreting flexible polyelectrolyte transport under nanoconfinement, with implications for polymer physics, nuclear pore transport, and intrinsically disordered proteins.