Open AccessHairpin-like siRNA-Based Spherical Nucleic Acids
Author(s) -
Matthew K Vasher,
Gokay Yamankurt,
Chad A. Mirkin
Publication year - 2022
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c12750
Subject(s) - small interfering rna , nucleic acid , chemistry , gene knockdown , rna interference , small hairpin rna , rna , biophysics , gene delivery , transfection , microbiology and biotechnology , nanotechnology , computational biology , biochemistry , gene , biology , materials science
The therapeutic use of small interfering RNAs (siRNAs) as gene regulation agents has been limited by their poor stability and delivery. Although arranging siRNAs into a spherical nucleic acid (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 hairpin-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 medical research.