A Generalizable Tension Sensor Platform for Mechanotherapeutic Discovery

Abstract

Mechanical forces are critical regulators of cellular function, and their modulation represents a promising therapeutic strategy across a range of diseases, including cancer and fibrosis. DNA-based molecular tension sensors (MTSs) have emerged as powerful tools for detecting receptor-specific cellular forces but remain limited by susceptibility to nuclease degradation and constrained ligand compatibility. Here, we outline these barriers to broader adoption and demonstrate how integrating established stabilization strategies effectively mitigates nuclease sensitivity. In addition, we introduce an engineered protein that covalently couples ligands to DNA in a modular, receptor-agnostic manner. Together, these innovations enable robust, nearly universal deployment of DNA-based MTSs across diverse experimental contexts and target proteins. We apply this enhanced platform to profile the mechanobiological effects of force-modulating drugs in both immortalized and primary cell lines. Unlike indirect or context-limited methods, this approach delivers direct, quantitative readouts of drug-induced changes in mechanical force transmission, offering a scalable path toward personalized mechanotherapeutic screening.