Molecular Chameleon Carriers for Nucleic Acid Delivery: The Sweet Spot between Lipoplexes and Polyplexes

Author:

Thalmayr Sophie1,Grau Melina1,Peng Lun1,Pöhmerer Jana1,Wilk Ulrich1,Folda Paul1,Yazdi Mina1,Weidinger Eric1,Burghardt Tobias1,Höhn Miriam1,Wagner Ernst1ORCID,Berger Simone1ORCID

Affiliation:

1. Pharmaceutical Biotechnology Center for Nanoscience Ludwig‐Maximilians‐Universität Munich Butenandtstrasse 5–13 81377 Munich Germany

Abstract

AbstractTaking advantage of effective intracellular delivery mechanisms of both cationizable lipids and polymers, highly potent double pH‐responsive nucleic acid carriers are generated by combining at least two lipo amino fatty acids (LAFs) as hydrophobic cationizable motifs with hydrophilic cationizable aminoethylene units into novel sequence‐defined molecules. The pH‐dependent tunable polarity of the LAF is successfully implemented by inserting a central tertiary amine, which disrupts the hydrophobic character once protonated, resulting in pH‐dependent structural and physical changes. This “molecular chameleon character” turns out to be advantageous for dynamic nucleic acid delivery via lipopolyplexes. By screening different topologies (blocks, bundles, T‐shapes, U‐shapes), LAF types, and LAF/aminoethylene ratios, highly potent pDNA, mRNA, and siRNA carriers are identified, which are up to several 100‐fold more efficient than previous carrier generations and characterized by very fast transfection kinetics. mRNA lipopolyplexes maintain high transfection activity in cell culture even in the presence of ≥90% serum at an ultra‐low mRNA dose of 3 picogram (≈2 nanoparticles/cell), and thus are comparable in potency to viral nanoparticles. Importantly, they show great in vivo performance with high expression levels especially in spleen, tumor, lungs, and liver upon intravenous administration of 1–3 µg luciferase‐encoding mRNA in mice.

Funder

Deutsche Forschungsgemeinschaft

Deutscher Akademischer Austauschdienst

China Scholarship Council

Publisher

Wiley

Subject

Mechanical Engineering,Mechanics of Materials,General Materials Science

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