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High-resolution bioenergetics correlates the length of continuous protonatable diaminoethane motif of four-armed oligo(ethanamino)amide transfectants to cytotoxicity

Lookup NU author(s): Professor Moein MoghimiORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023 The Author(s)Recent clinical success with Onpattro and cationic ionizable lipid nanoparticle-based mRNA vaccines has rejuvenated research in the design and engineering of broader synthetic cationic vectors for nucleic acid compaction and transfection. However, perturbation of metabolic processes and cytotoxicity are still of concern with synthetic cationic vectors. Here, through an integrated bioenergetic and biomembrane integrity probing in three different human cell lines we reveal the dynamic effect of a library of sequence-defined four-arm oligo(ethanamino)amide transfectant on cell homeostasis, and identify metabolically safe building units over wide concentration ranges. The results show differential effects of the oligo(ethanamino)amide structure of comparable molecular weight on cell energetics. The severity of polycation effect on bioenergetic crisis follows with the length of continuous protonatable diaminoethane motif in the ascending order of glutaryl-triethylene tetramine, succinyl-tetraethylene pentamine and succinyl-pentaethylene hexamine. We further identify oligomeric structures that do not induce bioenergetic crisis even at high concentrations. Finally, transfection studies with a library of polyplexes carrying a reporter gene show no correlation between transfection efficiency and cytotoxicity. These observations demonstrate the usefulness of integrated high-resolution respirometry and plasma membrane integrity probing as a highly sensitive medium-throughput screening strategy for identification and selection of safe building units for transfectant engineering.

Publication metadata

Author(s): Hall A, Bartek J, Wagner E, Lachelt U, Moghimi SM

Publication type: Article

Publication status: Published

Journal: Journal of Controlled Release

Year: 2023

Volume: 361

Pages: 115-129

Print publication date: 01/09/2023

Online publication date: 04/08/2023

Acceptance date: 30/07/2023

Date deposited: 12/09/2023

ISSN (print): 0168-3659

ISSN (electronic): 1873-4995

Publisher: Elsevier B.V.

URL: https://doi.org/10.1016/j.jconrel.2023.07.051

DOI: 10.1016/j.jconrel.2023.07.051

PubMed id: 37532151

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