Near‐infrared light (NIR; 650–900 nm) offers unparalleled advantages as a biocompatible stimulus. The development of photocages that operate in this region represents a fundamental challenge due to the low energy of the excitation light. Herein, we repurpose cyanine dyes into photocages that are available on a multigram scale in three steps and efficiently release carboxylic acids in aqueous media upon irradiation with NIR light up to 820 nm. The photouncaging process is examined using several techniques, providing evidence that it proceeds via photooxidative pathway. We demonstrate the practical utility in live HeLa cells by delivery and release of the carboxylic acid cargo, that was otherwise not uptaken by cells in its free form. In combination with modularity of the cyanine scaffold, the realization of these accessible photocages will fully unleash the potential of the emerging field of NIR‐photoactivation and facilitate its widespread adoption outside the photochemistry community.

Two new classes of near‐infrared molecular probes were prepared and shown to exhibit “turn on” fluorescence when cleaved by the nitroreductase enzyme, a well‐known biomarker of cell hypoxia. The fluorescent probes are heptamethine cyanine dyes with a central 4‘‐carboxylic ester group on the heptamethine chain that is converted by a self‐immolative fragmentation mechanism to a 4‘‐caboxylate group that greatly enhances the fluorescence brightness. Each compound was prepared by ring opening of a Zincke salt. The chemical structures have either terminal benzoindolinenes or propargyloxy auxochromes, which provide favorable red‐shifted absorption/emission wavelengths and a hyperchromic effect that enhances the photon output when excited by 808 nm light. A fluorescent probe with terminal propargyloxy‐indolenines exhibited less self‐aggregation and was rapidly activated by nitroreductase with large “turn on“ fluorescence; thus, it is the preferred choice for translation towards in vivo applications.

Near‐infrared light (NIR; 650–900 nm) offers unparalleled advantages as a biocompatible stimulus. The development of photocages that operate in this region represents a fundamental challenge due to the low energy of the excitation light. Herein, we repurpose cyanine dyes into photocages that are available on a multigram scale in three steps and efficiently release carboxylic acids in aqueous media upon irradiation with NIR light up to 820 nm. The photouncaging process is examined using several techniques, providing evidence that it proceeds via photooxidative pathway. We demonstrate the practical utility in live HeLa cells by delivery and release of the carboxylic acid cargo, that was otherwise not uptaken by cells in its free form. In combination with modularity of the cyanine scaffold, the realization of these accessible photocages will fully unleash the potential of the emerging field of NIR‐photoactivation and facilitate its widespread adoption outside the photochemistry community.

In this account, we provide an overview of the applications that arose from the recently developed synthetic methodology that delivers heptamethine cyanines (Cy7) substituted at the central chain. The ability to easily introduce and manipulate various substituents in different substitution patterns along the cyanine chain enabled rational tailoring of the photophysical and photochemical properties. Exercising this control over the structure–property relationship proved to have a substantial impact in the field of cyanine dyes and was swiftly harnessed in a number of emerging applications in distinct areas, including fluorescent probes, biosensors, dye-sensitized upconversion nanoparticles, phototruncation of cyanines and photocages. While this method unlocked a number of new avenues, many synthetic challenges remain to be conquered in order to fully capitalize on the potential of cyanines, and we provide a short perspective that summarizes them at the end of this manuscript.

The Front Cover illustrates the action of a cyanine‐based fluorescent probe inside a hypoxic A549 cell. Nitroreductase enzyme, a well‐known biomarker of hypoxia, transforms a carboxylic ester group on the central heptamethine chain through a self‐immolative fragmentation mechanism into a brightly fluorescent carboxylate group, resulting in a “turn on” fluorescent response. The cell elements were provided by Reactome.org under the CC BY 4.0 license. More information can be found in the Research Article by P. Štacko, B. D. Smith et al.