Molecular jackhammers induce intracellular calcium release and skeletal muscle contraction by vibronic-driven action

Intracellular calcium release (ICR) is of fundamental importance for numerous physiological and pathological processes, from cell differentiation to neurotransmitter release and muscle contraction. The ability to precisely control ICR is crucial for understanding cellular signaling mechanisms and developing therapeutic interventions for calcium-related disorders. Light-induced ICR offers numerous advantages over conventional approaches, including superior specificity, precise spatiotemporal control, excellent reproducibility, and minimal invasiveness. Here, we demonstrate that cyanine dyes function as molecular jackhammers (MJHs) to induce ICR in human embryonic kidney (HEK) 293 and immortalized mouse myoblast C2C12 cells through vibronic-driven action (VDA) following red light (640 nm) activation. VDA generates longitudinally and axially coordinated whole-molecule vibrations, enabling mechanical interactions with cells. Structure-activity relationship studies of twenty synthesized MJHs demonstrated that sulfonate-containing derivatives most effectively triggered intracellular calcium release while exhibiting minimal cytotoxicity. Mechanistic studies showed that MJH-induced calcium release operates through the inositol-triphosphate (IP₃) pathway rather than reactive oxygen species generation. Finally, we demonstrated light-activated MJH-induced calcium waves in vivo using transgenic Hydra vulgaris expressing a fluorescent calcium indicator. This work establishes MJHs as molecular-scale devices for remote control of cellular signaling, expanding the utility of cyanine dyes for modulating physiological processes with potential therapeutic applications.