Spherical Nucleic Acid Probe Based on 2′-Fluorinated DNA Functionalization for High-Fidelity Intracellular Sensing

Traditional spherical nucleic acids (SNAs) based on gold nanoparticles (AuNPs) assembled through Au–S covalent bonds are widely used in DNA-programmable assembly, biosensing, imaging, and therapeutics. However, biological thiols and other chemical substances can break the Au–S bonds and cause response distortion during the application process, specifically in cell environments. Herein, we report a new type of SNAs based on 2′-fluorinated DNA-functionalized AuNPs with excellent colloidal stability under high salt conditions (up to 1 M NaCl) and over a broad pH range (1–14), as well as resistance to biothiols. The fluorinated spherical nucleic acid probe (Au/FDNA probe) could detect targeted cancer cells with high fidelity. Compared to the traditional thiolated DNA-functionalized AuNP probe (Au–SDNA probe), the Au/FDNA probe exhibited a higher sensitivity to the target and a lower signal-to-background ratio. Furthermore, the Au/FDNA probe could discriminate target cancer cells in a mixed culture system. Using the proposed FDNA functionalization method, previously developed SNAs based on AuNPs could be directly adapted, which might open a new avenue for the design and application of SNAs.