The Golden Touch by Light: A Finely Engineered Luminogen Empowering High Photoactivatable and Photodynamic Efficiency for Cancer Phototheranostics

Abstract Photoactivatable agent is a powerful tool in biomedicine studies due to high‐precision spatiotemporal control of light. However, those previously reported agents generally suffer from short wavelength, fluorescence self‐quenching effect, and the lack of photosensitizing property, which severely restrict their practical applications. To address these issues, molecular engineering of 1,4‐dihydropyridine derivatives is conducted to obtain an optimized agent, namely TPA‐DHPy‐Py, which exhibits low oxidation potential, high photoactivation efficiency, and excellent type I/II combined photodynamic activity. Concurrently, its photoactivated counterpart is featured by aggregation‐induced near‐infrared emission and remarkable reactive oxygen species (ROS) production efficiency. Upon photoactivation, TPA‐DHPy‐Py is capable of precisely identifying cancer cells from co‐culturing cancer cells and normal cells without the assistance of any extra targeting units, and in situ monitoring lipid droplets and endoplasmic reticulum alteration under ROS stress, as well as achieving fluorescent visualization of tumor in vivo with supremely high imaging contrast. Furthermore, the unprecedented performance on photodynamic cancer therapy is demonstrated by the significant inhibition of tumor growth. Therefore, the photoactivatable TPA‐DHPy‐Py with dual‐organelle‐targeted and excellent photodynamic activity associated with self‐monitoring ability is highly promising for cancer theranostics in clinical trials.