Precise photorelease in living cells by high-viscosity activatable coumarin-based photocages

Intracellular viscosity is a critical microenvironmental factor in various biological systems, and its abnormal increase is closely linked to the progression of many diseases. Therefore, precisely controlling the release of bioactive molecules in high-viscosity regions is vital for understanding disease mechanisms and advancing their diagnosis and treatment. However, viscosity alone cannot directly trigger chemical reactions. Inspired by molecular rotor fluorophores, we have developed a series of high-viscosity activated photocages by modifying the C3 position of the coumarin scaffold with electron-withdrawing groups. In low-viscosity environments, both fluorescence and photocleavage of the photocages are inhibited by nonradiative decay caused by intramolecular free rotation. In contrast, in high-viscosity environments, the restriction of this intramolecular rotation restores fluorescence and photocleavage. These unique photolysis properties enable the selective photorelease of these photocages in high-viscosity conditions. As a proof of concept, we have developed a drug delivery system that targets abnormal mitochondria with high viscosity. This system demonstrates enhanced photolysis efficiency in abnormal mitochondria compared to normal ones, allowing for precise drug release in diseased mitochondria while ensuring excellent biological safety in healthy mitochondria. We anticipate that these photocages will serve as convenient and efficient tools for the precise release of active molecules in high-viscosity environments.