Rapid Thermal Drying Synthesis of Nonthiolated Spherical Nucleic Acids with Stability Rivaling Thiolated DNA

Attaching DNA oligonucleotides to gold nanoparticles (AuNPs) to prepare spherical nucleic acids (SNAs) has offered tremendous insights into biointerface chemistry with resulting bioconjugates serving as critical reagents in biosensors and nanotechnology. While thiolated DNA is generally required to achieve stable conjugates, we herein communicate that using a thermal drying method, a high DNA density and excellent SNA stability was achieved using nonthiolated DNA, rivaling the performance of thiolated DNA such as surviving 1 M NaCl, 2 month stability in 0.3 M NaCl and working in 50% serum. A poly‐adenine block with as few as two consecutive terminal adenine bases is sufficient for anchoring on AuNPs. By side‐by‐side comparison with the salt‐aging method, the conjugation mechanism was attributed to competitive adenine adsorption at high temperature along with an extremely high DNA concentration upon drying. Bioanalytical applications of the nonthiolated SNAs were validated in both solution and paper‐based sensor platforms, facilitating cost‐effective applications for SNAs.