» Articles » PMID: 29432194

Structurally Modulated Codelivery of SiRNA and Argonaute 2 for Enhanced RNA Interference

Overview
Specialty Science
Date 2018 Feb 13
PMID 29432194
Citations 19
Authors
Affiliations
Soon will be listed here.
Abstract

Small interfering RNA (siRNA) represents a promising class of inhibitors in both fundamental research and the clinic. Numerous delivery vehicles have been developed to facilitate siRNA delivery. Nevertheless, achieving highly potent RNA interference (RNAi) toward clinical translation requires efficient formation of RNA-induced gene-silencing complex (RISC) in the cytoplasm. Here we coencapsulate siRNA and the central RNAi effector protein Argonaute 2 (Ago2) via different delivery carriers as a platform to augment RNAi. The physical clustering between siRNA and Ago2 is found to be indispensable for enhanced RNAi. Moreover, by utilizing polyamines bearing the same backbone but distinct cationic side-group arrangements of ethylene diamine repeats as the delivery vehicles, we find that the molecular structure of these polyamines modulates the degree of siRNA/Ago2-mediated improvement of RNAi. We apply this strategy to silence the oncogene STAT3 and significantly prolong survival in mice challenged with melanoma. Our findings suggest a paradigm for RNAi via the synergistic coassembly of RNA with helper proteins.

Citing Articles

Advances in nucleic acid delivery strategies for diabetic wound therapy.

Sarthi S, Bhardwaj H, Jangde R J Clin Transl Endocrinol. 2024; 37:100366.

PMID: 39286540 PMC: 11404062. DOI: 10.1016/j.jcte.2024.100366.


A tiny loop in the Argonaute PIWI domain tunes small RNA seed strength.

Xiao Y, Liu T, MacRae I EMBO Rep. 2023; 24(6):e55806.

PMID: 37082939 PMC: 10240194. DOI: 10.15252/embr.202255806.


Cytoplasmic delivery of siRNA using human-derived membrane penetration-enhancing peptide.

Nakamura M, Fujiwara K, Doi N J Nanobiotechnology. 2022; 20(1):458.

PMID: 36303212 PMC: 9615171. DOI: 10.1186/s12951-022-01667-4.


Circular RNA Fbxl5 Regulates Cardiomyocyte Apoptosis During Ischemia Reperfusion Injury via Sponging microRNA-146a.

Li D, You J, Mao C, Zhou E, Han Z, Zhang J J Inflamm Res. 2022; 15:2539-2550.

PMID: 35479829 PMC: 9037744. DOI: 10.2147/JIR.S360129.


Lipid Nanoparticle-mRNA Formulations for Therapeutic Applications.

Wang C, Zhang Y, Dong Y Acc Chem Res. 2021; 54(23):4283-4293.

PMID: 34793124 PMC: 10068911. DOI: 10.1021/acs.accounts.1c00550.


References
1.
Mok H, Lee S, Park J, Park T . Multimeric small interfering ribonucleic acid for highly efficient sequence-specific gene silencing. Nat Mater. 2010; 9(3):272-8. DOI: 10.1038/nmat2626. View

2.
Aini H, Itaka K, Fujisawa A, Uchida H, Uchida S, Fukushima S . Messenger RNA delivery of a cartilage-anabolic transcription factor as a disease-modifying strategy for osteoarthritis treatment. Sci Rep. 2016; 6:18743. PMC: 4700530. DOI: 10.1038/srep18743. View

3.
Leuschner F, Dutta P, Gorbatov R, Novobrantseva T, Donahoe J, Courties G . Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 2011; 29(11):1005-10. PMC: 3212614. DOI: 10.1038/nbt.1989. View

4.
Uchida H, Itaka K, Nomoto T, Ishii T, Suma T, Ikegami M . Modulated protonation of side chain aminoethylene repeats in N-substituted polyaspartamides promotes mRNA transfection. J Am Chem Soc. 2014; 136(35):12396-405. DOI: 10.1021/ja506194z. View

5.
Leuschner P, Ameres S, Kueng S, Martinez J . Cleavage of the siRNA passenger strand during RISC assembly in human cells. EMBO Rep. 2006; 7(3):314-20. PMC: 1456892. DOI: 10.1038/sj.embor.7400637. View