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Journal of Nanomaterials
Volume 2011 (2011), Article ID 742895, 12 pages
Review Article

Nanoparticles Escaping RES and Endosome: Challenges for siRNA Delivery for Cancer Therapy

Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA

Received 24 May 2011; Accepted 30 June 2011

Academic Editor: Xing J. Liang

Copyright © 2011 Shutao Guo and Leaf Huang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Small interfering RNAs (siRNAs) technology has emerged as a promising potential treatment for viral, genetic diseases and cancers. Despite the powerful therapeutic potential of siRNA, there are challenges for developing efficient and specific delivery systems for systemic administration. There are extracellular and intracellular barriers for nanoparticle-mediated delivery. First, nanoparticles are rapidly cleared from the circulation by the reticuloendothelial system (RES). Second, following their cellular uptake, nanoparticles are trapped in endosomes/lysosomes, where siRNA would be degraded by enzymes. In this review, we describe strategies for grafting a polyethylene glycol (PEG) brush to the nanoparticles for evading RES, such that they may effectively accumulate in the tumor by the enhanced permeability and retention (EPR) effect. PEG has to shed from the nanoparticles to allow close interaction with the tumor cells. Current strategies for facilitating endosome escape, such as ion pair formation, “proton sponge effect”, destabilizing endosome membrane, and hydrophobic modification of the vector, are discussed.