Disulfide-Mediated siRNA Delivery System based on in situ Polymerization for Synergistic Antitumor Therapy

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 vehicles is required to overcome the limitations. Herein, we designed a smart siRNA delivery system based on in situ polymerization of disulfide monomer. A nanocomplex is created through the supramolecular assembly of cationic di-thiol monomer featuring a quaternary-ammonium-modified triphenylphosphonium (TPP) moiety and polyanionic siRNA. The siRNA acts as template for in situ disulfide-mediated polymerization. The disulfide-based nanocomplex display enhanced cellular uptake ability via thiol-mediated uptake and stability. After internalization, the disulfide bond of polymer is reduced under the high GSH concentration in the tumor microenvironment and reduction of disulfide bonds induce decomplexation and the siRNA release into the cytosol. In a previous study, we have reported that the cationic di-thiol monomers easily accumulate in mitochondria, which induces polymeric disulfide formation under the high level of reactive oxygen species (ROS). We expect the smart nanocomplex could be candidate for combinational therapy induced by gene silencing and intramitochondrial polymerization.