Redox-Sensitive Gelatin/Silica-Aptamer Nanogels for Targeted siRNA Delivery

Abstract RNA interference (RNAi) has potential advantages over other gene therapy approaches due to its high specificity and the ability to inhibit target gene expression. However, the stability and tissue-specific delivery of siRNA remain as the biggest obstacles for RNAi therapeutics. Here, we developed such a system by conjugating gelatin-based nanogels with the nucleolin-targeted AS1411 aptamer and deoxynucleotide-substituted siRNA together (Apt-GS/siRNA) via a disulfide linker to achieve transient docking of siRNA. These Apt-GS/siRNA nanogels demonstrated favorable release of siRNA under reducing conditions owing to disulfide cleavage. Furthermore, this smart system could electively release siRNA into the cytosol in nucleolin-positive cells (A549) by a glutathione-triggered disassembly and subsequently efficient RNAi for luciferase. Besides, disulfide-equipped Apt-GS nanogels showed good biocompatibility in vitro. Taken together, this redox-responsive, tumor-targeting smart nanogels display great potential in exploiting functionalized siRNA delivery and tumor therapy.