Journal
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
Volume 12, Issue 5, Pages 1323-1334Publisher
ELSEVIER
DOI: 10.1016/j.nano.2016.02.003
Keywords
siRNA delivery; Nanocomplex; Hepatic stellate cells; Intracellular trafficking; Exocytosis
Funding
- National Institute of Health [1R01AA021510]
- UMKC Office of Research Services, UMKC Center of Excellence in Dental and Musculoskeletal Tissues
- NIH [S10RR027668]
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Despite the importance of siRNA delivery systems, understanding of their intracellular fate remains elusive. We recently developed a multi-component siRNA nanocomplex to deliver siRNA to hepatic stellate cells (HSCs). The objective of this study is to study post-internalization trafficking of this siRNA nanocomplex and its multiple components like siRNA, protamine, and streptavidin, in HSCs. After internalization, the nanocomplex entrapped in early endosomes undergoes three possible routes including endosomal escape, exocytosis, and entrapment in lysosomes. Significant amount of siRNA dissociates from the nanocomplex to exert silencing activity. After escaping from endosomes, protamine dissociates from the nanocomplex and stays inside the cytoplasm. Golgi complex plays an important role in exocytosis of the nanocomplex. We also demonstrate that exocytosis is one of the major reasons accounting for the transient silencing activity of nonviral siRNA delivery. Incorporation of exocytosis inhibitors in nonviral siRNA delivery systems may extend the silencing activity of siRNA. (C) 2016 Elsevier Inc. All rights reserved.
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