Minimalist Design of a Stimuli-Responsive Spherical Nucleic Acid for Conditional Delivery of Oligonucleotide Therapeutics.

In this work, we report a component-minimal spherical nucleic acid (SNA) from monodisperse DNA-polymer conjugates that can load and release nucleic acid therapeutics in a stimuli-responsive manner. We show that this vehicle assembles from only four strands, and conditional release of its antisense therapeutic cargo can be induced upon recognition of specific oligonucleotide triggers via strand displacement. The latter (triggers) may be a microRNA that offers additional synergistic therapy, in addition to the previously shown ability of the SNA to load hydrophobic drugs. The SNA is easy to prepare, has dynamic character, releases its cargo only upon the presence of both triggers, and can survive biological conditions while protecting its cargo. The gene silencing potency of the cargo was tested in live cells and shown to be suppressed when loaded in the SNA, and its activity was restored only upon release with the two triggers. This vehicle has the essential characteristics of versatility, ease of synthesis, low cost, highly responsive behavior, and ability to support combination therapies, making it a promising candidate for cell-selective drug delivery and clinical transition.