An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile
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An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile Dinesh Dhumal1,§, Wenjun Lan1,2,§, Ling Ding1,3,§, Yifan Jiang1, Zhenbin Lyu1,4, Erik Laurini5, Domenico Marson5, Aura Tintaru4, Nelson Dusetti2, Suzanne Giorgio1, Juan Lucio Iovanna2, Sabrina Pricl5,6, and Ling Peng1 () 1
Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UMR 7325, Equipe Labellisée Ligue Contre le Cancer, Marseille 13288, France 2 Aix-Marseille Université, INSERM, CNRS, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille 13288, France 3 Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale (CRMBM), UMR 7339, Marseille 13385, France 4 Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, Marseille 13013, France 5 Molecular Biology and Nanotechnology Laboratory, Department of Engineering and Architectures, University of Trieste, Trieste 34127, Italy 6 Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-136, Poland § Dinesh Dhumal, Wenjun Lan, and Ling Ding contributed equally to this work. © Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 20 August 2020 / Revised: 28 October 2020 / Accepted: 31 October 2020
ABSTRACT Gene therapy using small interfering RNA (siRNA) is emerging as a novel therapeutic approach to treat various diseases. However, safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics. Here we report an ionizable supramolecular dendrimer vector, formed via self-assembly of a small amphiphilic dendrimer, as an effective siRNA delivery system with a favorable safety profile. By virtue of the ionizable tertiary amine terminals, the supramolecular dendrimer has a low positively charged surface potential and no notable cytotoxicity at physiological pH. Nonetheless, this ionizable feature imparted sufficient surface charge to the supramolecular dendrimer to enable formation of a stable complex with siRNA via electrostatic interactions. The resulting siRNA/dendrimer delivery system had a surface charge that was neither neutral, thus avoiding aggregation, nor too high, thus avoiding cytotoxicity, but was sufficient for favorable cellular uptake and endosomal release of the siRNA. When tested in different cancer cell lines and patient-derived cancer organoids, this dendrimer-mediated siRNA delivery system effectively silenced the oncogenes Myc and Akt2 with a potent antiproliferative effect, outperforming the gold standard vector, Lipofectamine 2000. Therefore, this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery. The concept of supramolecular dendrimer nanovectors via self-assembly is new, yet easy to implement in practice, offering a new perspective for supramolecular chemistry in biomedical applications.
KEYWORDS dendrimer, self-ass
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