PubReading [221] - Hairpin-like siRNA-Based Spherical Nucleic Acids - M. Vasher, G. Yamankurt, C. Mirkin

<p>The therapeutic use of <strong>small interfering RNA</strong>s (siRNAs) as gene regulation agents has been limited by their poor stability and delivery. Although arranging siRNAs into a <strong>spherical nucleic acid</strong> (SNA) architecture to form siRNA-SNAs increases their stability and uptake, prototypical siRNA-SNAs consist of a hybridized architecture that causes guide strand dissociation from passenger strands, which limits the delivery of active siRNA duplexes. In this study, a new SNA design that directly attaches both siRNA strands to the SNA core through a single hairpin-shaped molecule to prevent guide strand dissociation is introduced and investigated. This <strong>hairpin</strong>-like architecture increases the number of siRNA duplexes that can be loaded onto an SNA by 4-fold compared to the original hybridized siRNA-SNA architecture. As a result, the hairpin-like siRNA-SNAs exhibit a 6-fold longer half-life in serum and decreased cytotoxicity. In addition, the hairpin-like siRNA-SNA produces more durable gene knockdown than the hybridized siRNA-SNA. This study shows how the chemistry used to immobilize siRNA on nanoparticles can markedly enhance biological function, and it establishes the hairpin-like architecture as a next-generation SNA construct that will be useful in life science and <strong>medical research</strong>.</p><p><em>DOI: </em><a href="https://doi.org/10.1021/jacs.1c12750"><em>10.1021/jacs.1c12750 - 2022</em></a></p>