Oligonucleotides are powerful molecules for programming
function
and assembly. When arrayed on nanoparticle scaffolds in high density,
the resulting molecules, spherical nucleic acids (SNAs), become imbued
with unique properties. We used the copper-catalyzed azide–alkyne
cycloaddition to graft oligonucleotides on Qβ virus-like particles
to see if such structures also gain SNA-like behavior. Copper-binding
ligands were shown to promote the click reaction without degrading
oligonucleotide substrates. Reactions were first optimized with a
small-molecule fluorogenic reporter and were then applied to the more
challenging synthesis of polyvalent protein nanoparticle–oligonucleotide
conjugates. The resulting particles exhibited the enhanced cellular
uptake and protection from nuclease-mediated oligonucleotide cleavage
characteristic of SNAs, had similar residence time in the liver relative
to unmodified particles, and were somewhat shielded from immune recognition,
resulting in nearly 10-fold lower antibody titers relative to unmodified
particles. Oligonucleotide-functionalized virus-like particles thus
provide an interesting option for protein nanoparticle-mediated delivery
of functional molecules.