Reactive Glycolysis Metabolite‐Activatable Nanotheranostics for NIR‐II Fluorescence Imaging‐Guided Phototherapy of Cancer

Abstract Second near‐infrared (NIR‐II) fluorescence imaging with deep tissue‐penetration ability holds remarkable potential for cancer diagnosis. However, clinical translation of NIR‐II fluorescence imaging‐based cancer treatment is severely restricted by the low signal‐to‐background ratio due to insufficient tumor specificity of fluorophores. In this study, it is hypothesized that methylglyoxal (MGO), an intermediate metabolite of tumor glycolysis could be used as a potent biomarker for triggering NIR‐II fluorescence imaging‐guided cancer theranostic. For proof‐of‐concept, first a MGO‐activatable NIR‐II fluorescence probe is developed, and then MGO‐responsive “dual lock‐and‐key” nanotheranostics by integrating the NIR‐II fluorophore and a photodynamic prodrug (i.e., hexyl 5‐aminolevulinic acid hydrochloride (HAL)) into one nanoparticle is engineered. The nanotheranostic can be specifically activated with tumorous MGO for NIR‐II fluorescence imaging‐guided combinatory cancer therapy. Upon 808 nm laser irradiation, the activated NIR‐II fluorophore can generate tunable photothermal effect to trigger HAL release. Subsequently, HAL is converted to protoporphyrin IX inside the tumor cells for 655 nm laser irradiation‐induced photodynamic therapy. It is demonstrated that the NIR‐II fluorescence nanotheranostics is highly specifically activated in the tumor and efficiently suppressed 4T1 breast tumor growth in mouse model. The NIR‐II fluorescence imaging‐based nanotheranostic might imply novel insight into reactive metabolite‐activatable precise therapy of tumor.