Cationic Micelles Outperform Linear Polymers for Delivery of Antisense Oligonucleotides in Serum: An Exploration of Polymer Architecture, Cationic Moieties, and Cell Addition Order

Mckenna G Hanson, Christian J Grimme, Cristiam F Santa Chalarca, Theresa M. Reineke

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8 Scopus citations


Antisense oligonucleotides (ASOs) are an important emerging therapeutic; however, they struggle to enter cells without a delivery vehicle, such as a cationic polymer. To understand the role of polymer architecture for ASO delivery, five linear polymers and five diblock polymers (capable of self-assembly into micelles) were synthesized with varying cationic groups. After complexation of each polymer/micelle with ASO, it was found that less bulky cationic moieties transfected the ASO more effectively. Interestingly, however the ASO internalization trend was the opposite of the transfection trend for cationic moiety, indicating internalization is not the major factor in determining transfection efficiency for this series. Micelleplexes (micelle-ASO complexes) generally enable higher transfection efficacy as compared to polyplexes (linear polymer-ASO complexes). Additionally, the order of addition of cells and complexes was explored. Linear polyplexes showed better transfection efficiency in adhered cells, whereas micelleplexes delivered the ASO more efficiently when the cells and micelleplexes were added simultaneously. This phenomenon may be due to increased cell-complex interactions as micelleplexes have increased colloidal stability compared to polyplexes. These findings emphasize the importance of polymer composition and architecture in governing the cellular interactions necessary for transfection, thus allowing advancement in the design principles for nonviral nucleic acid delivery formulations.

Original languageEnglish (US)
Pages (from-to)2121-2131
Number of pages11
JournalBioconjugate Chemistry
Issue number11
StatePublished - Nov 16 2022

Bibliographical note

Funding Information:
We sincerely thank Genentech for funding of this work. M.G.H. acknowledges the support from the National Science Foundation Graduate Research Fellowship Program (DGE-1839286) and the University of Minnesota Doctoral Dissertation Fellowship. This work was also supported by the National Science Foundation (NSF) through the University of Minnesota MRSEC under award DMR2011401. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. The authors would like to express their gratitude toward Dr. Karthik Nagaoudi and Dr. Apoorva Sarode from Genentech for numerous helpful discussions. We would also like to thank Kaelyn Gasvoda, Dr. Eben Alsberg, Dr. Qiaobing Xu, Liu Yang for helpful discussions regarding ASO knockdown assay development and in particular Dr. Eben Alsberg for donating the deGFP HEK cells to our laboratory. We are grateful to Hannah Lembke for her help with statistical analysis. Parts of this work’s figures were adapted or created with BioRender.

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© 2022 American Chemical Society. All rights reserved.

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