Coenzyme Q10 (CoQ10), also known as ubiquinone (UQ), serves as mitochondrial antioxidant whose deficiency allows reactive oxygen species (ROS) level to raise, causing insulin resistance and ultimately various cardiometabolic disorders.1 Therefore, CoQ10 is identified as a therapeutic agent, supplement of which to the mitochondria can prevent its subsequent diseases.2 CoQ10 has low oral bioavailability due to its lipophilic nature and large molecular weight. To overcome this, several mitochondrially targeting cations (MTCs) have been reported for localization of CoQ10 to the mitochondrial matrix. Nevertheless, direct conjugation of CoQ10 to MTCs has been shown to loses its biological functions3, highlighting the need for alternative delivery approaches that retain CoQ10 function while enabling controlled mitochondrial release.
In this context, we are developing fluorescent probes conjugated to CoQ10 via cleavable linkers that respond to distinct biological or external stimuli. Such stimulus-responsive probes enable spatiotemporally controlled release of CoQ10 while simultaneously allowing us to visualise probe activation within mitochondria. As a representative example, we synthesised rhodamine-based fluorescent probes in which CoQ10 is linked via a ROS-sensitive cleavable linker. Rhodamine serves both as a mito-targeting and a fluorescence reporter. Under elevated ROS conditions, ROS-sensitive linker cleavage induces a fluorescence turn-on response accompanied by the release of active CoQ10. This approach enables ROS-triggered CoQ10 delivery with real-time fluorescence monitoring, offering a promising tool for investigating mitochondrial oxidative stress and laying the foundations for future drug development.