Self‐Initiated Nano‐Micelles Mediated Covalent Modification of mRNA for Labeling and Treatment of Tumors
Yong Li, Xiao‐Ling Lei, Xiao‐Shuai Zhang, Bin Zhang, Yong‐Guo Hu, Meng Guan, Kai Cheng, Wei Chen, Bo Liu, Jin‐Xuan Fan, Yuan‐Di Zhao
Abstract
Abstract As a promising gene therapy strategy, controllable small molecule‐mRNA covalent modification in tumor cells could be initiated by singlet oxygen ( 1 O 2 ) to complete the modification process. However, in vivo generation of 1 O 2 is usually dependent on excitation of external light, and the limited light penetration of tissues greatly interferes the development of deep tumor photo therapy. Here, we constructed a tumor‐targeting nano‐micelle for the spontaneous intracellular generation of 1 O 2 without the need for external light, and inducing a high level of covalent modification of mRNA in tumor cells. Luminol and Ce6 were chemically bonded to produce 1 O 2 by chemiluminescence resonance energy transfer (CRET) triggered by high levels of hydrogen peroxide (H 2 O 2 ) in the tumor microenvironment (TME). The sufficient 1 O 2 oxidized the loaded furan to highly reactive dicarbonyl moiety, which underwent cycloaddition reaction with adenine (A), cytosine (C) or guanine (G) on the mRNA for interfering with the tumor cell protein expression, thereby inhibiting tumor progression. In vitro and in vivo experiments demonstrated that this self‐initiated gene therapy nano‐micelle could induce covalent modification of mRNA by 1 O 2 without external light, and the process could be monitored in real time by fluorescence imaging, which provided an effective strategy for RNA‐based tumor gene therapy.