Loading…

Self‐Initiated Nano‐Micelles Mediated Covalent Modification of mRNA for Labeling and Treatment of Tumors

As a promising gene therapy strategy, controllable small molecule‐mRNA covalent modification in tumor cells could be initiated by singlet oxygen (1O2) to complete the modification process. However, in vivo generation of 1O2 is usually dependent on excitation of external light, and the limited light...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie 2024-12, Vol.136 (50), p.n/a
Main Authors: Li, Yong, Lei, Xiao‐Ling, Zhang, Xiao‐Shuai, Zhang, Bin, Hu, Yong‐Guo, Guan, Meng, Cheng, Kai, Chen, Wei, Liu, Bo, Fan, Jin‐Xuan, Zhao, Yuan‐Di
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:As a promising gene therapy strategy, controllable small molecule‐mRNA covalent modification in tumor cells could be initiated by singlet oxygen (1O2) to complete the modification process. However, in vivo generation of 1O2 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 1O2 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 1O2 by chemiluminescence resonance energy transfer (CRET) triggered by high levels of hydrogen peroxide (H2O2) in the tumor microenvironment (TME). The sufficient 1O2 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 1O2 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. Achieving in situ spontaneous and precise mRNA covalent modification can effectively interfere with the translation of mRNA in tumor cells, thereby inhibiting tumor growth. The linked Luminol and Ce6 generated 1O2 in situ by CRET and furan‐mediated covalent modification of mRNAs was triggered for RNA interference in situ. This strategy offers novel insights into in situ RNA interference.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202411598