2′-Fluoro-substituted DNA-induced self-assembly strategy for engineering hybrid nanospheres

The physicochemical differences between DNA and other molecules pose a challenge to the construction of DNA-based nanostructures. Herein, we propose a straightforward approach for preparing multifunctional DNA-based nanospheres through direct self-assembly of 2′-fluoro-substituted single-stranded DNA (2′F-DNA) with various small molecules. Molecular dynamics simulation revealed that 2′F substitution in DNA can cause the repulsion of adjacent PO43- group, leading to local stretching of the DNA structure. Moreover, 2′F substituent induced the regular polarization of H2O nearby F to form the hydration layer, which interrupts inherent interactions among bases. In this way, the bases of 2′F-DNA chain have fewer constraints and more flexibility in conformation, facilitating their non-covalent interactions with other molecules and enhancing the self-assembly capacity of 2′F-DNA. Consequently, 2′F-DNA can bind to more molecules, tending to spontaneously form hybrid DNA nanospheres. Following this approach, a chemo-gene therapy 2′F-DNA/doxorubicin model was designed, showing the significant synergistic anti-tumor therapeutic efficacy. Taken together, this study provides an expandable approach for constructing engineering hybrid nanospheres using DNA and other small molecules, which holds great potential for further biological applications.