Review of the Historical and Technical Development of DNA Based Single-molecule Force Sensors

Abstract

Mechanobiology has evolved from macroscopic anatomical studies to a precise molecular understanding of how cells sense and respond to physical forces. While conventional tools like atomic force microscopy and traction force microscopy established the field, they often face trade-offs between force sensitivity and high-throughput spatial mapping in living cells. This review explores the transformative rise of DNA-based single-molecule force sensors, which leverage the programmability and defined physical attributes of nucleic acids to bridge this gap. We critically analyze the design principles and mechanical characteristics of four primary sensor classes: DNA duplexes, DNA hairpins, DNA origami, and DNA G-quadruplexes. Special attention is given to their fabrication and tuning for detecting piconewton-scale events. Furthermore, we highlight versatile applications ranging from dissecting cellular mechanotransduction to high-resolution bioimaging and biosensing. Finally, we discuss recent advances, projecting a future era of "mechano-medicine" where active DNA nanodevices profile mechanical phenotypes for diagnostic and therapeutic innovation.