Journal
ACTA BIOMATERIALIA
Volume 23, Issue -, Pages 136-146Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2015.05.028
Keywords
Gold nanorods; Disulfide-linked polyethylenimine; Glutathione; RGD peptide; RNA delivery
Funding
- National Natural Science Foundation of China (NSFC) [81171439]
- National Basic Research Program of China (973 Program) [2010CB529902]
- National Key Technology R&D Program of the Ministry of Science and Technology [2012BAI18B01]
- European Research Council via a Marie Curie International Incoming Fellowship [PIIF-GA-2012-331281]
- EPSRC [EP/K039202/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/K039202/1] Funding Source: researchfish
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RNA interference (RNAi) mediated gene silencing holds significant promises in gene therapy. A major obstacle to efficient RNAi is the systemic delivery of the therapeutic RNAs into the cytoplasmon without being trapped in intracellular endo-/lyso-somes. Herein we report the development of a PEGylated, RGD peptide modified, and disulfide cross-linked short polyethylenimines (DSPEIs) functionalized gold nanorod (RDG) for targeted small hairpin (sh)RNA delivery. The RDG effectively condensed shRNAs into stable nanoparticles, allowing for highly specific targeting of model human brain cancer cells (U-87 MG-GFP) via the alpha(v)beta(3) integrins-mediated endocytosis. The combined effects of endosomal escape (via the proton-sponge effect of the PEIs) and efficient cleavage of the disulfide-cross-linked DSPEIs by the high intracellular glutathione content triggered rapid cytoplasma shRNAs release resulting in excellent RNAi efficiency and low cytotoxicity. Furthermore, the high stability and prolonged blood circulation afforded by PEGylation allowed for highly effective, targeted tumor accumulation and internalization of the carriers, resulting in outstanding intra-tumor gene silencing efficiency in U-87 MG-GFP tumor bearing BALB/c mice. Combining the capabilities of both passive and active targeting, intracellular glutathione-triggered off-on release and endosomal escape, the RDG nanocarrier developed herein appears to be a highly promising non-viral vector for efficient RNAi. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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