Alkaline Phosphatase-Controllable and Red Light-Activated RNA Modification Approach for Precise Tumor Suppression

RNA interference (RNAi) has proved to be a promising modality for disease treatment. However, the promise of conventional RNA therapeutics for clinical application is severely impeded by low delivery efficiency and susceptibility of RNAs to serum RNases. Therefore, developing advanced RNAi technolog...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Chemical Society 2022-12, Vol.144 (50), p.23061-23072
Main Authors: Fang, Jing, Feng, Yali, Zhang, Yuqi, Wang, Anna, Li, Jiachen, Cui, Chaoxiang, Guo, Yirui, Zhu, Jinfeng, Lv, Zhengzhong, Zhao, Zhongsheng, Xu, Chenjie, Shi, Haibin
Format: Article
Language:English
Subjects:
Alkaline Phosphatase
Fluorescent Dyes - chemistry
Humans
Light
Neoplasms
RNA
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:RNA interference (RNAi) has proved to be a promising modality for disease treatment. However, the promise of conventional RNA therapeutics for clinical application is severely impeded by low delivery efficiency and susceptibility of RNAs to serum RNases. Therefore, developing advanced RNAi technology is an increasing demand for achieving precise medicine. Herein, for the first time, we propose an alkaline phosphatase (ALP)-controllable and red light-activated RNA modification (ALARM) approach for anti-tumor therapeutic application. An ALP-responsive NIR fluorogenic probe f-RCP consisting of a tumor-targeting cyclic RGD peptide, an ALP-activated photosensitizer CyOP, and an 1O2-susceptible furan module for RNA modification was rationally designed and synthesized. Studies have demonstrated that f-RCP can specifically target to liver carcinoma HepG2 cells and spontaneously emit activated NIR/photoacoustic signals upon cleavage by the ALP enzyme, allowing for sensitive detection of ALP-positive tumors. More notably, we surprisingly found that the capability of f-RCP producing singlet oxygen (1O2) under red light irradiation could be simultaneously unlocked, which can ignite the covalent cyclization reaction between furan and nucleobases of intracellular RNA molecules, leading to significant mitochondrial damage and severe apoptosis of tumor cells, in consequence realizing efficient tumor suppression. Most importantly, the potential therapeutic mechanism was first explored on the transcriptomic level. This delicate ALARM strategy may open up new insights into cancer gene therapy.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.2c10409