Preparation and Biological Properties of Oligonucleotide-Functionalized Virus-like Particles

Oligonucleotides are powerful molecules for programmingfunctionand assembly. When arrayed on nanoparticle scaffolds in high density,the resulting molecules, spherical nucleic acids (SNAs), become imbuedwith unique properties. We used the copper-catalyzed azide-alkynecycloaddition to graft oligonucleotides on Q beta virus-like particlesto see if such structures also gain SNA-like behavior. Copper-bindingligands were shown to promote the click reaction without degradingoligonucleotide substrates. Reactions were first optimized with asmall-molecule fluorogenic reporter and were then applied to the morechallenging synthesis of polyvalent protein nanoparticle-oligonucleotideconjugates. The resulting particles exhibited the enhanced cellularuptake and protection from nuclease-mediated oligonucleotide cleavagecharacteristic of SNAs, had similar residence time in the liver relativeto unmodified particles, and were somewhat shielded from immune recognition,resulting in nearly 10-fold lower antibody titers relative to unmodifiedparticles. Oligonucleotide-functionalized virus-like particles thusprovide an interesting option for protein nanoparticle-mediated deliveryof functional molecules.

Automated summary

By using the copper-catalyzed azide-alkyne cycloaddition, oligonucleotides were grafted onto Q beta virus-like particles, resulting in spherical nucleic acids (SNAs) with enhanced cellular uptake, protection from nuclease-mediated degradation, and reduced immune recognition. Oligonucleotide-functionalized virus-like particles provide a new option for protein nanoparticle-mediated delivery of functional molecules.