Modularized Gold Nanocarriers for TAT-Mediated Delivery of siRNA

Abstract

Targeted delivery of siRNA controlled by near-infrared light using hollow gold nanoshells has been demonstrated in cancer and stem cells models. Here, a universal surface module and several functionalization rules for the maximized delivery of short nucleic acids (here, siRNA) applicable for diverse gold nanocarriers are described. Streptavidin is devised as a handle to assemble biotinylated cell penetrating peptides (e.g., transactivating transcriptional activator (TAT)), as well as an insulator between the positive charge of TAT and the dense negative charge of RNA. However, direct linking of streptavidin to functional siRNA inhibits its silencing activity. The approach then involves the orthogonal assembly of two types of RNA strands: one with biotin modification for cell targeting and penetration (scaffold RNA); the other without biotin as functional RNA (i.e., siRNA). Initially, flexible single-stranded RNA is used for dense surface-packing, followed by hybridization with the complementary RNA strand to maximize the assembly of the targeting peptide for cellular uptake and siRNA delivery. This orthogonal approach for the delivery of short oligonucleotides, together with novel surface functionalization rules discovered here, should enable the use of these materials for nanomedicinal research and applications.