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Histone-targeted Polyplexes Avoid Endosomal Escape and Enter the Nucleus During Postmitotic Redistribution of ER Membranes.

Abstract：

:Nonviral gene delivery is a promising therapeutic approach because of its safety and controllability, yet limited gene transfer efficacy is a common issue. Most nonviral strategies rely upon endosomal escape designs; however, endosomal escape is often uncorrelated with improved gene transfer and membranolytic structures are typically cytotoxic. Previously, we showed that histone-targeted polyplexes trafficked to the nucleus through an alternative route involving caveolae and the Golgi and endoplasmic reticulum (ER), using pathways similar to several pathogens. We hypothesized that the efficacy of these polyplexes was due to an increased utilization of native vesicular trafficking as well as regulation by histone effectors. Accordingly, using confocal microscopy and cellular fractionation, we determined that a key effect of histone-targeting was to route polyplexes away from clathrin-mediated recycling pathways by harnessing endomembrane transfer routes regulated by histone methyltransferases. An unprecedented finding was that polyplexes accumulated in Rab6-labeled Golgi/ER vesicles and ultimately shuttled directly into the nucleus during ER-mediated nuclear envelope reassembly. Specifically, super resolution microscopy and fluorescence correlation spectroscopy unequivocally indicated that the polyplexes remained associated with ER vesicles/membranes until mitosis, when they were redistributed into the nucleus. These novel findings highlight alternative mechanisms to subvert endolysosomal trafficking and harness the ER to enhance gene transfer.

journal_name

Mol Ther Nucleic Acids

journal_title

Molecular therapy. Nucleic acids

authors

Ross NL,Munsell EV,Sabanayagam C,Sullivan MO

doi

10.1038/mtna.2015.2

subject

Has Abstract

pub_date

2015-02-10 00:00:00

pages

e226

issn

2162-2531

pii

mtna20152

journal_volume

4

pub_type

杂志文章

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