Ultrafast Near‐Infrared Light‐Triggered Intracellular Uncaging to Probe Cell Signaling

The possibility of regulating cell signaling with high spatial and temporal resolution within individual cells and complex cellular networks has important implications in biomedicine. This article demonstrates a general strategy that uses near‐infrared tissue‐penetrating laser pulses to uncage biomolecules from plasmonic gold‐coated liposomes, i.e., plasmonic liposomes, to activate cell signaling in a nonthermal, ultrafast, and highly controllable fashion. Near‐infrared picosecond laser pulse induces transient nanobubbles around plasmonic liposomes. The mechanical force generated from the collapse of nanobubbles rapidly ejects encapsulated compound within 0.1 ms. This article shows that single pulse irradiation triggers the rapid intracellular uncaging of calcein from plasmonic liposomes inside endolysosomes. The uncaged calcein then evenly distributes over the entire cytosol and nucleus. Furthermore, this article demonstrates the ability to trigger calcium signaling in both an immortalized cell line and primary dorsal root ganglion neurons by intracellular uncaging of inositol triphosphate (IP 3 ), an endogenous cell calcium signaling second messenger. Compared with other uncaging techniques, this ultrafast near‐infrared light‐driven molecular uncaging method is easily adaptable to deliver a wide range of bioactive molecules with an ultrafast optical switch, enabling new possibilities to investigate signaling pathways within individual cells and cellular networks.