Cyanine‐Flavonol Hybrids for Near‐Infrared Light‐Activated Delivery of Carbon Monoxide

Carbon monoxide (CO) is an endogenous signaling molecule that controls a number of physiological processes. To circumvent the inherent toxicity of CO, light‐activated CO‐releasing molecules (photoCORMs) have emerged as an alternative for its administration. However, their wider application requires photoactivation using biologically benign visible and near‐infrared (NIR) light. In this work, a strategy to access such photoCORMs by fusing two CO‐releasing flavonol moieties with a NIR‐absorbing cyanine dye is presented. These hybrids liberate two molecules of CO in high chemical yields upon activation with NIR light up to 820 nm and exhibit excellent uncaging cross‐sections, which surpass the state‐of‐the‐art by two orders of magnitude. Furthermore, the biocompatibility and applicability of the system in vitro and in vivo are demonstrated, and a mechanism of CO release is proposed. It is hoped that this strategy will stimulate the discovery of new classes of photoCORMs and accelerate the translation of CO‐based phototherapy into practice. CO worker: Carbon monoxide (CO) is a signaling molecule with potent therapeutic properties hampered by its inherent toxicity. Here, cross‐breeding a CO‐releasing flavonol moiety with heptamethine cyanine dye leads to highly efficient transition‐metal‐free photoCORMs (CO‐releasing molecules). These photoCORMs operate in the middle of the phototherapeutic window, release two molecules of CO upon irradiation, and are shown to be applicable in vivo.