mRNA-responsive two-in-one nanodrug for enhanced anti-tumor chemo-gene therapy

Yongfei Liu; Yuhong Lin; Han Xiao; Zhangcheng Fu; Xiaohui Zhu; Xiaoyong Chen; Chunsen Li; Chenyu Ding; Chunhua Lu

doi:10.1016/j.jconrel.2024.04.007

mRNA-responsive two-in-one nanodrug for enhanced anti-tumor chemo-gene therapy

J Control Release. 2024 Apr 15:369:765-774. doi: 10.1016/j.jconrel.2024.04.007. Online ahead of print.

Authors

Yongfei Liu¹, Yuhong Lin², Han Xiao³, Zhangcheng Fu⁴, Xiaohui Zhu⁴, Xiaoyong Chen⁵, Chunsen Li⁶, Chenyu Ding⁷, Chunhua Lu⁸

Affiliations

¹ Department of Neurosurgery, Fujian Institute of Brain Disorders and Brain Science, Fujian Clinical Research Center for Neurological Diseases, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, PR China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, PR China; MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, Fuzhou University, Fuzhou, Fujian 350116, PR China.
² MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, Fuzhou University, Fuzhou, Fujian 350116, PR China; Zhejiang Provincial Key Laboratory of Plant Evolutionary Ecology and Conservation, Taizhou Key Laboratory of Biomedicine and Advanced Dosage Forms, School of Life Sciences, Taizhou University, Taizhou, Zhejiang 318000, PR China.
³ State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, PR China.
⁴ MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, Fuzhou University, Fuzhou, Fujian 350116, PR China.
⁵ Department of Neurosurgery, Fujian Institute of Brain Disorders and Brain Science, Fujian Clinical Research Center for Neurological Diseases, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, PR China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, PR China.
⁶ State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, PR China. Electronic address: chunsen.li@fjirsm.ac.cn.
⁷ Department of Neurosurgery, Fujian Institute of Brain Disorders and Brain Science, Fujian Clinical Research Center for Neurological Diseases, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, PR China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, PR China. Electronic address: dingcydr@163.com.
⁸ Department of Neurosurgery, Fujian Institute of Brain Disorders and Brain Science, Fujian Clinical Research Center for Neurological Diseases, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, PR China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, PR China; MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, Fuzhou University, Fuzhou, Fujian 350116, PR China. Electronic address: chunhualu@fzu.edu.cn.

PMID: 38593976
DOI: 10.1016/j.jconrel.2024.04.007

Abstract

The combination of chemotherapy and gene therapy holds great promise for the treatment and eradication of tumors. However, due to significant differences in physicochemical properties between chemotherapeutic agents and functional nucleic acid drugs, direct integration into a single nano-agent is hindered, impeding the design and construction of an effective co-delivery nano-platform for synergistic anti-tumor treatments. In this study, we have developed an mRNA-responsive two-in-one nano-drug for effective anti-tumor therapy by the direct self-assembly of 2'-fluoro-substituted antisense DNA against P-glycoprotein (2'F-DNA) and chemo drug paclitaxel (PTX). The 2'-fluoro modification of DNA could significantly increase the interaction between the therapeutic nucleic acid and the chemotherapeutic drug, promoting the successful formation of 2'F-DNA/PTX nanospheres (2'F-DNA/PTX NSs). Due to the one-step self-assembly process without additional carrier materials, the prepared 2'F-DNA/PTX NSs exhibited considerable loading efficiency and bioavailability of PTX. In the presence of endogenous P-glycoprotein mRNA, the 2'F-DNA/PTX NSs were disassembled. The released 2'F-DNA could down-regulate the expression of P-glycoprotein, which decreased the multidrug resistance of tumor cells and enhanced the chemotherapy effect caused by PTX. In this way, the 2'F-DNA/PTX NSs could synergistically induce the apoptosis of tumor cells and realize the combined anti-tumor therapy. This strategy might provide a new tool to explore functional intracellular co-delivery nano-systems with high bioavailability and exhibit potential promising in the applications of accurate diagnosis and treatment of tumors.

Keywords: Carrier-free; Chemotherapy; Gene silence; Nano-drug; Synergistic treatment.