Advancing Spherical Nucleic Acid Synthesis in Less‐Polar Solvents

Abstract Spherical nucleic acids (SNAs) are radially packed, highly dense DNA “forests” on nanoparticle cores, depicting a useful class of artificially engineered bionanomaterials. The widespread uses of SNAs in diverse chemistry and nanotechnology areas have driven their synthetic innovations toward reduced time/cost and ever‐improved quality. Different from existing methods based on salt‐aging, low‐pH, freezing, and dehydration conditions, herein a speedy and facile way is reported to produce SNAs in miscible aqueous‐alcoholic media with easily adjustable solvent polarities. Critically, it is discovered that the non‐aqueous environment of a water/isopropanol (IPA) mixture plays a vital role in affecting DNA interaction with gold nanoparticles (AuNPs) via different surface‐anchoring groups. In addition to significantly accelerated DNA conjugation on AuNPs, the IPA‐based strategy achieves various unprecedented controls on the formation of SNAs. These unique features include enhanced DNA adsorption (and ligand desorption) on AuNPs and the possibility of using gold‐alkyne linkage for a rapid SNA preparation. Highly efficient SNA syntheses are achieved based on unmodified, thiolated, and alkynated DNA. Moreover, solvent‐programmed directionality control of DNA grafts on AuNPs is realized based on alkyne/phosphorothioate dual‐functionalities, which is otherwise unrealizable. The high effectiveness of the IPA‐based method points to a previously unconsidered microenvironment‐related DNA‐nanoparticle interaction for innovating SNA synthesis.