Polyplex Evolution: Understanding Biology, Optimizing Performance

Arnaldur Hall, Ulrich Lächelt, Jiri Bartek, Ernst Wagner, Seyed Moein Moghimi

Research output: Contribution to journalReview articlepeer-review

158 Scopus citations

Abstract

Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is accompanied by serious cytotoxic complications and safety concerns at innate immune levels, which impedes the development of therapeutic polycationic nucleic acid carriers in general and their clinical applications. In recent years, the dilemma between transfection efficacy and adverse PEI activities has been addressed from in-depth investigations of cellular processes during transfection and elucidation of molecular mechanisms of PEI-mediated toxicity and translation of these integrated events to chemical engineering of novel PEI derivatives with an improved benefit-to-risk ratio. This review addresses these perspectives and discusses molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity, including membrane destabilization, mitochondrial dysfunction, and perturbations of glycolytic flux and redox homeostasis as well as chemical strategies for the generation of better tolerated polycations. We further examine the effect of PEI and its derivatives on complement activation and interaction with Toll-like receptors. These perspectives are intended to lay the foundation for an improved understanding of interlinked mechanisms controlling transfection and toxicity and their translation for improved engineering of polycation-based transfectants.

Original languageEnglish (US)
Pages (from-to)1476-1490
Number of pages15
JournalMolecular Therapy
Volume25
Issue number7
DOIs
StatePublished - Jul 5 2017

Keywords

  • complement system
  • cytotoxicity
  • mitochondrion
  • polyethylenimine
  • polyplex

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Polyplex Evolution: Understanding Biology, Optimizing Performance'. Together they form a unique fingerprint.

Cite this