Targeting the Blind Spot of Polycationic Nanocarrier-based SiRNA Delivery

Overview

Journal ACS Nano

Publisher American Chemical Society

Specialty Biotechnology

Date 2012 Oct 6

PMID 23036046

Citations 38

Authors

Mengyao Zheng

Giovanni M Pavan

Manuel Neeb

Andreas K Schaper

Andrea Danani

Gerhard Klebe

Olivia M Merkel

Thomas Kissel

Affiliations

Soon will be listed here.

Abstract

Polycationic nanocarriers attract increasing attention to the field of siRNA delivery. We investigated the self-assembly of siRNA vs pDNA with polycations, which are broadly used for nonviral gene and siRNA delivery. Although polyethyleneimine (PEI) was routinely adopted as siRNA carrier based on its efficacy in delivering pDNA, it has not been investigated yet why PEI efficiently delivers pDNA to cells but is controversially discussed in terms of efficacy for siRNA delivery. We are the first to investigate the self-assembly of PEI/siRNA vs PEI/pDNA and the steps of complexation and aggregation through different levels of hierarchy on the atomic and molecular scale with the novel synergistic use of molecular modeling, molecular dynamics simulation, isothermal titration calorimetry, and other characterization techniques. We are also the fist to elucidate atomic interactions, size, shape, stoichiometry, and association dynamics for polyplexes containing siRNA vs pDNA. Our investigation highlights differences in the hierarchical mechanism of formation of related polycation-siRNA and polycation-pDNA complexes. The results of fluorescence quenching assays indicated a biphasic behavior of siRNA binding with polycations where molecular reorganization of the siRNA within the polycations occurred at lower N/P ratios (nitrogen/phosphorus). Our results, for the first time, emphasize a biphasic behavior in siRNA complexation and the importance of low N/P ratios, which allow for excellent siRNA delivery efficiency. Our investigation highlights the formulation of siRNA complexes from a thermodynamic point of view and opens new perspectives to advance the rational design of new siRNA delivery systems.

Citing Articles

Molecular Dynamics Simulations Elucidate the Molecular Organization of Poly(beta-amino ester) Based Polyplexes for siRNA Delivery.

Steinegger K, Allmendinger L, Sturm S, Sieber-Schafer F, Kromer A, Muller-Caspary K Nano Lett. 2024; 24(49):15683-15692.

PMID: 39592142 PMC: 11638951. DOI: 10.1021/acs.nanolett.4c04291.

Closing the Gap between Experiment and Simulation─A Holistic Study on the Complexation of Small Interfering RNAs with Polyethylenimine.

Binder J, Winkeljann J, Steinegger K, Trnovec L, Orekhova D, Zahringer J Mol Pharm. 2024; 21(5):2163-2175.

PMID: 38373164 PMC: 7616749. DOI: 10.1021/acs.molpharmaceut.3c00747.

Pulmonary siRNA Delivery with Sophisticated Amphiphilic Poly(Spermine Acrylamides) for the Treatment of Lung Fibrosis.

Adams F, Zimmermann C, Baldassi D, Pehl T, Weingarten P, Kachel I Small. 2023; 20(22):e2308775.

PMID: 38126895 PMC: 7616748. DOI: 10.1002/smll.202308775.

Engineering poly- and micelleplexes for nucleic acid delivery - A reflection on their endosomal escape.

Winkeljann B, Keul D, Merkel O J Control Release. 2022; 353:518-534.

PMID: 36496051 PMC: 9900387. DOI: 10.1016/j.jconrel.2022.12.008.

Characterization of the Interaction of Polymeric Micelles with siRNA: A Combined Experimental and Molecular Dynamics Study.

Marquet F, Stojceski F, Grasso G, Patrulea V, Danani A, Borchard G Polymers (Basel). 2022; 14(20).

PMID: 36297986 PMC: 9611052. DOI: 10.3390/polym14204409.

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