Smart siRNA Delivery System based on Stimuli-Responsive Disulfide Polymer

Abstract

siRNA (small interfering RNA), which interferes with gene expression by inhibiting the production of specific proteins, has great potential for treatment of human diseases, especially malignant cancers. However, delivering siRNA into target cell cytosol remains challenging due to the biological barriers as poor stability and low endosomal escape efficiency. Thus, a rational design of siRNA carriers is required to overcome the limitations. Herein, we designed a smart siRNA delivery system based on stimuli-responsive disulfide polymer. A nanocomplex is created through the supramolecular assembly of cationic disulfide polymer featuring a quaternary-ammonium-modified triphenylphosphonium (TPP) moiety and polyanionic siRNA. The cationic nanocomplex display enhanced cellular uptake ability and stability. After internalization, the disulfide bond of polymer is reduced under the high GSH concentration in the tumor microenvironment and nanocomplex dissociation makes siRNA release into the cytosol. In a previous study, we have reported that the cationic monomers easily accumulate in mitochondria, which induces polymeric disulfide formation under the high level of reactive oxygen species (ROS). We expect the smart nanocomplex give rise to dual therapeutic effects induced by gene silencing and intramitochondrial polymerization.