New tool for diseases mechanism studies: Endoplasmic reticulum-targeted fluorescent probes

The endoplasmic reticulum (ER) is one of the most important organelles in cells, involved in protein synthesis, folding, and modification, as well as Ca2+ storage and release. ER homeostasis imbalances may contribute to various diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and cancer. Current research efforts primarily focus on ER-related disease mechanisms and drug candidate screening. Because disease processes involve multiple molecular events and signaling, an innovative tool is necessary to precisely detect key signaling molecules in the ER to accelerate the discovery of targeted therapeutics. In recent years, because of their real-time visualization, precise targeting, high sensitivity and specificity, low cytotoxicity, and synthetic tunability, fluorescent probes have been widely used to investigate biological processes and disease events. This review first introduces ER and its related biological processes, and the design rules of ER-targeted probes. Subsequently, based on the latest literature, it systematically summarizes the research progress of fluorescent probes for imaging physiological or pathological events in the ER. Lastly, it discusses the challenges of ER-targeted probes as well as the future development of probe engineering. We anticipate that this review will not only encourage the development of fluorescence probe engineering but will also enhance interdisciplinary research between chemistry, biology, pharmacology, and medicine, promoting for its widespread application.