Polycation Architecture and Assembly Direct Successful Gene Delivery: Micelleplexes Outperform Polyplexes via Optimal DNA Packaging

Zhe Tan, Yaming Jiang, Wenjia Zhang, Logan Karls, Timothy P. Lodge, Theresa M. Reineke

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Cellular delivery of biomacromolecules is vital to medical research and therapeutic development. Cationic polymers are promising and affordable candidate vehicles for these precious payloads. However, the impact of polycation architecture and solution assembly on the biological mechanisms and efficacy of these vehicles has not been clearly defined. In this study, four polymers containing the same cationic poly(2-(dimethylamino)ethyl methacrylate) (D) block but placed in different architectures have been synthesized, characterized, and compared for cargo binding and biological performance. The D homopolymer and its diblock copolymer poly(ethylene glycol)-block-poly(2-(dimethylamino) ethyl methacrylate) (OD) readily encapsulate pDNA to form polyplexes. Two amphiphilic block polymer variants, poly(2-(dimethylamino)ethyl methacrylate)-block-poly(n-butyl methacrylate) (DB) and poly(ethylene glycol)-block-poly(2-(dimethylamino)ethyl methacrylate)-block-poly(n-butyl methacrylate) (ODB), self-assemble into micelles, which template pDNA winding around the cationic corona to form micelleplexes. Micelleplexes were found to have superior delivery efficiency compared to polyplexes and detailed physicochemical and biological characterizations were performed to pinpoint the mechanisms by testing hypotheses related to cellular internalization, intracellular trafficking, and pDNA unpackaging. For the first time, we find that the higher concentration of amines housed in micelleplexes stimulates both cellular internalization and potential endosomal escape, and the physical motif of pDNA winding into micelleplexes, reminiscent of DNA compaction by histones in chromatin, preserves the pDNA secondary structure in its native B form. This likely allows greater payload accessibility for protein expression with micelleplexes compared to polyplexes, which tightly condense pDNA and significantly distort its helicity. This work provides important guidance for the design of successful biomolecular delivery systems via optimizing the physicochemical properties.

Original languageEnglish (US)
Pages (from-to)15804-15817
Number of pages14
JournalJournal of the American Chemical Society
Volume141
Issue number40
DOIs
StatePublished - Oct 9 2019

Bibliographical note

Funding Information:
This work was supported primarily by the National Science Foundation through the University of Minnesota MRSEC under Award Number DMR-1420013. Part of this work was carried out in the College of Science and Engineering Characterization Facility, University of Minnesota, which has received capital equipment funding from NSF through the UMN MRSEC program under Award Number DMR-1420013. Circular dichroism spectroscopy experiments were performed at the Biophysical Technology Center, University of Minnesota Department of Biochemistry, Molecular Biology, and Biophysics. We thank Lisa Zeeb and Joseph Hexum from the University of Minnesota for their help with graphic generation.

How much support was provided by MRSEC?

  • Primary

Reporting period for MRSEC

  • Period 6

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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