Precise and Mechanical Control of Calcium Signaling in Muscle Cells by Near-Infrared-Activated Molecular Jackhammers.

Abstract

Light-stimulated control of intracellular calcium signaling offers precise spatial and temporal control with minimal invasiveness, making it a powerful strategy for modulating cellular functions. We introduce here a class of cyanine-based molecular jackhammers (MJHs) that harness vibronic-driven action (VDA) to induce rapid and controllable calcium release under near-infrared (NIR) irradiation. A library of 19 structurally diverse MJHs was synthesized, among which the sulfonated derivative showed the highest efficacy for calcium release and lowest cytotoxicity. Photodynamic and photothermal contributions are shown to be inconsequential to the mechanism of action. This was done using reactive oxygen species scavengers, genetically encoded temperature indicators, and pharmacological inhibitors. The mechanism is consistent with activation of the inositol trisphosphate (IP₃) pathway in MJH-induced calcium release. Notably, calcium release was consistently observed across three distinct muscle cell types, with skeletal myotubes exhibiting robust contractile responses upon MJH activation. Comparative studies in 3D spheroid models highlighted the effective tissue penetration of NIR light and the advantages of MJHs over previously developed Feringa-type molecular motors in inducing calcium release. These findings indicate that MJHs enable noninvasive and precise modulation of calcium dynamics, with broad potential in both fundamental research and therapeutic applications.