Size‐Dependent Ultrasound Activation of Thrombin Catalytic Activity by Mechano‐Nanoswitches

Abstract Integrating nanostructures with mechanochemistry significantly boosts drug loading capabilities and sonomechanical drug activation, outperforming traditional polymer systems. Nevertheless, the influence of nanoparticles’ physicochemical properties on their mechanochemical responses remains largely unexplored. In this work, different‐sized mechano‐nanoswitches consisting of two gold nanoparticles (5, 10, and 20 nm), which are bridged by a single DNA strand that is harboring a thrombin binding site loaded with the enzyme, are constructed to investigate the relationship between size and force responsiveness under ultrasound. When subjected to ultrasonication, these nanoswitches are stretched and unfolded, triggering the release and catalytic activation of thrombin. The results demonstrate that the largest nanoswitches (20 nm) exhibit the most pronounced ultrasound responsiveness, reaching up to two times that of the smallest nanoswitches (5 nm). This investigation deepens the basic understanding of the critical role of the size of colloidal nanoparticles in mechanochemistry and offers valuable insights for developing novel mechanoresponsive nanostructures, paving the way for more efficient mechanically controlled drug or protein activation strategies.