Supramolecular Assembly of Polyphenols and Nucleic Acids by Thermal Cycling for Immune Cell Activation

Supramolecular assembly of polyphenols and biomacromolecules (proteins and nucleic acids) has emerged as a versatile and simple strategy to construct nanomaterials with biological activity. Here, we report a strategy to finely control the supramolecular assembly of tannic acid and oligonucleotides into uniform and stable nanoparticles by exploiting the thermal cycling of tannic acid. The equilibrium of complexation is investigated, and individual nanoparticles are resolved with nanoscale resolution by using stochastic optical reconstruction microscopy. The nanoparticles incorporating cytosine phosphoguanine (CpG) oligonucleotides are efficiently taken up by cells and trafficked via endo/lysosomal compartments and induce up to a 7-fold increase in tumor necrosis factor secretion in RAW 264.7 macrophage cells compared with naked CpG oligonucleotides. This work highlights the potential of this simple approach to engineer two-component tannic acid-oligonucleotide nanoparticles for the intracellular delivery of therapeutic nucleic acids.