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. 2022 Oct 20;12(1):17520.
doi: 10.1038/s41598-022-22509-1.

Investigation of the ionic conditions in SiRNA-mediated delivery through its carriers in the cell membrane: a molecular dynamic simulation

Mohammad Hasan Darvishi  1 , Abdollah Allahverdi  2 , Hadi Hashemzadeh  2 , Hamid Reza Javadi  3
Affiliations

Investigation of the ionic conditions in SiRNA-mediated delivery through its carriers in the cell membrane: a molecular dynamic simulation

Mohammad Hasan Darvishi et al. Sci Rep. .

Abstract

SiRNA is a new generation of drug molecules and a new approach for treating a variety of diseases such as cancer and viral infections. SiRNA delivery to cells and translocation into cytoplasm are the main challenges in the clinical application of siRNA. Lipid carriers are one of the most successful carriers for siRNA delivery. In this study, we investigated the interaction of siRNA with a zwitterionic bilayer and how ion concentration and lipid conjugation can affect it. The divalent cation such as Mg2+ ions could promote the siRNA adsorption on the bilayer surface. The cation ions can bind to the head groups of lipids and the grooves of siRNA molecules and form bridges between the siRNA and bilayer surface. Our findings demonstrated the bridges formed by divalent ions could facilitate the attachment of siRNA to the membrane surface. We showed that the divalent cations can regulate the bridging-driven membrane attachment and it seems the result of this modulation can be used for designing biomimetic devices. In the following, we examined the effect of cations on the interaction between siRNA modified by cholesterol and the membrane surface. Our MD simulations showed that in the presence of Mg2+, the electrostatic and vdW energy between the membrane and siRNA were higher compared to those in the presence of NA+. We showed that the electrostatic interaction between membrane and siRNA cannot be facilitated only by cholesterol conjugated. Indeed, cations are essential to create coulomb repulsion and enable membrane attachment. This study provides important insight into liposome carriers for siRNA delivery and could help us in the development of siRNA-based therapeutics. Due to the coronavirus pandemic outbreak, these results may shed light on the new approach for treating these diseases and their molecular details.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
(A) The structure prediction and refinement of siRNA and the building membrane, (B) Schematic representation of the liposome-RNA complex and the bilayer—RNA system, which is a model for studying siRNA adsorption on the membrane surface.
Figure 2
Figure 2
The distance between the center of mass bilayer and siRNA in the absence and presence of Mg2+ ions.
Figure 3
Figure 3
The number of contacts between siRNA and the membrane in the presence of monovalent and divalent cations.
Figure 4
Figure 4
The distribution of divalent cations in the siRNA—membrane system. The purple line is related to the density of Mg ions. In the range of 3–6 nm of z coordinate, the density of Mg ions is around zero because of the hydrophobic region of the membrane.
Figure 5
Figure 5
The presentation of the lipid bilayer and siRNA in the presence of Mg2+ ions that surrounded it using VMD (A) and (B) pictures are related to the adsorption of siRNA molecules on the membrane, which is surrounded by Mg2+ ions. Many Mg2+ ions were located at minor and major grooves of siRNA which can affect the structure of RNA.
Figure 6
Figure 6
The root mean score fluctuation (RMSF) of siRNA in the presence of Mg2+ ions and in the presence of monovalent ions. The siRNA is double stranded. Each chain of the siRNA has 23 nucleotides.
Figure 7
Figure 7
The distance between the center of mass of siRNA modified by cholesterol and head group lipids during the MD simulation.
Figure 8
Figure 8
(A) The electrostatic and (B) vdW energy between the siRNA-cholesterol-conjugate system and lipid bilayer in the presence of Mg2+ ions and in the presence of monovalent ions.
Figure 9
Figure 9
The number of contacts between siRNA-cholesterol-conjugate system–lipid bilayer.
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References

    1. Hu B, Zhong L, Weng Y, Peng L, Huang Y, Zhao Y, et al. Therapeutic siRNA: State of the art. Signal Transduct. Target. Ther. 2020;5(1):1–25. doi: 10.1038/s41392-020-0207-x. - DOI - PMC - PubMed
    1. Zeng Y, Yi R, Cullen BR. MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc. Natl. Acad. Sci. 2003;100(17):9779–9784. doi: 10.1073/pnas.1630797100. - DOI - PMC - PubMed
    1. Devi G. siRNA-based approaches in cancer therapy. Cancer Gene Ther. 2006;13(9):819–829. doi: 10.1038/sj.cgt.7700931. - DOI - PubMed
    1. Oh Y-K, Park TG. siRNA delivery systems for cancer treatment. Adv. Drug Deliv. Rev. 2009;61(10):850–862. doi: 10.1016/j.addr.2009.04.018. - DOI - PubMed
    1. Singh A, Trivedi P, Jain NK. Advances in siRNA delivery in cancer therapy. Artif. cells nanomed. biotechnol. 2018;46(2):274–283. doi: 10.1080/21691401.2017.1307210. - DOI - PubMed
-