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Issue 48, 2016, Issue in Progress
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Enhancing intracranial delivery of clinically relevant non-viral gene vectors

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Gene therapy is a promising strategy for the management of various neurological disorders that do not respond adequately to conventional therapeutics. The development of gene vectors with favorable safety profiles that can achieve uniform distribution and high-level transgene expression in the brain remains challenging. The rod-shaped, non-viral gene delivery platform based on poly-L-lysine (PLL) conjugated to a single segment of polyethylene glycol (PEG) has shown safe transfection in human nares and mouse brains in vivo. However, we have previously demonstrated that a denser PEG coating is required for rapid diffusion of nanoparticles in the brain extracellular space. Here, we engineered a densely PEGylated version of this platform based on PLL polymers conjugated to branched PEG via alkyne-azide cycloaddition. We found that the newly developed gene vectors rapidly diffused in the brain parenchyma, providing significantly improved vector distribution and overall transgene expression in vivo compared to the previously developed platform. These brain-penetrating DNA nanoparticles exhibited enhanced cellular uptake presumably due to their ellipsoidal morphology. By simultaneously improving delivery to target cells and subsequent transfection, our densely PEGylated PLL DNA nanoparticles can provide widespread, high levels of transgene expression, essential for effective targeting of highly disseminated brain diseases.

Graphical abstract: Enhancing intracranial delivery of clinically relevant non-viral gene vectors

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Supplementary files

Article information

18 Jan 2016
12 Apr 2016
First published
19 Apr 2016

RSC Adv., 2016,6, 41665-41674
Article type
Author version available

Enhancing intracranial delivery of clinically relevant non-viral gene vectors

S. Berry, P. Mastorakos, C. Zhang, E. Song, H. Patel, J. S. Suk and J. Hanes, RSC Adv., 2016, 6, 41665
DOI: 10.1039/C6RA01546H

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