Tetrahedral DNA Framework‐Based Spherical Nucleic Acids for Efficient siRNA Delivery

Abstract Spherical nucleic acids (SNAs) hold substantial therapeutic potential for the delivery of small interfering RNAs (siRNAs). Nevertheless, their potential remains largely untapped due to the challenges of cytosolic delivery. Inspired by the dynamic, spiky architecture of coronavirus, an interface engineering approach based on a tetrahedral DNA framework (tDF) is demonstrated for the development of coronavirus‐mimicking SNAs. By exploiting their robustness and precise construction, tDFs are evenly arranged on the surface of core nanoparticles (NPs) with flexible conformations, generating a dynamic, spiky architecture. This spiky architecture in tetrahedral DNA framework‐based SNAs (tDF‐SNAs) substantially improve siRNAs duplex efficiency from 20 % to 95 %. Meanwhile, tDF‐SNAs changed the endocytosis pathway to clathrin‐independent cellular engulfment pathway and enhanced the cellular uptake efficiency. Due to these advances, the delivery efficiency of siRNA molecules by tDF‐SNAs is 1–2 orders of magnitude higher than that of SNAs, resulting in a 2‐fold increase in gene silencing efficacy. These results show promise in the development of bioinspired siRNAs delivery systems for intracellular applications.