Smart siRNA Nanomedicine for Synergistic effect through Intramitochondrial Polymerization and Gene Silencing

Abstract

Small interfering RNA (siRNA) holds tremendous potential for the treatment of various human diseases. However, its clinical translation has been hindered by challenges in achieving effective cytosolic delivery to target cells. The inherent complexities and dynamic cellular mechanisms often limit the therapeutic efficacy, as siRNA-induced gene knockdown alone may not trigger sufficient cell death. Herein, we proposed a sophisticated siRNA nanomedicine with intelligent features, enabling efficient intracellular delivery, overcoming endosome escape barriers, and activating cell death signals. The nanomedicine establishes close interactions with the cell membrane, facilitating escape from endosomes/lysosomes. Additionally, the nanomedicine utilizes disulfide-based intramitochondrial polymerization, inducing mitochondrial damage to trigger the apoptotic mechanism. The novel paradigm of "Carrier-Synergy" suggest a synergistic effect through the intracellular self-assembly and gene silencing.