Short oligonucleotide sequences are now being widely investigated for their potential therapeutic properties. The modification of oligonucleotide termini with short fluorinated residues is capable of drastically altering their behavior in complex in vitro and in vivo systems, and thus may serve to greatly enhance their therapeutic potential. The main goals of our work were to explore: 1) how modification of STAT3 transcription factor-binding oligodeoxynucleotide (ODN) duplexes (ODND) with one or two short fluorocarbon (FC)-based residues would change their properties in vitro and in vivo, and if so, how this would affect their intracellular uptake by cancer cells, and 2) the ability of such modified ODND to form non-covalent complexes with FC-modified carrier macromolecule. The latter has an inherent advantage of producing a 19F-specific magnetic resonance (MR) imaging signature. Thus, we also tested the ability of such copolymers to generate 19F-MR signals. Materials and Methods. Fluorinated nucleic acid residues were incorporated into ODN by using automated synthesis or via activated esters on ODN 5'-ends. To quantify ODND uptake by the cells and to track their stability, we covalently labeled ODN with fluorophores using internucleoside linker technology; the FC-modified carrier was synthesized by acylation of pegylated polylysine graft copolymer with perfluoroundecanoic acid (M5-gPLL-PFUDA). Results. ODN with a single FC group exhibited a tendency to form duplexes with higher melting points and with increased stability against degradation when compared to control non-modified ODNs. ODND carrying fluorinated residues showed complex formation with M5-gPLL-PFUDA as predicted by molecular dynamics simulations. Moreover, FC groups modulated the specificity of ODND binding to the STAT3 target. Finally, FC modification resulted in greater cell uptake (2 to 4 fold higher) when compared to the uptake of non-modified ODND as determined by quantitative confocal fluorescence imaging of A431 and INS-1 cells. Conclusion. ODND modification with FC residues enables fine-tuning of protein binding specificity to double-strand binding motifs and results in an increased internalization by A431 and INS-1 cells in culture. Our results show that modification of ODN termini with FC residues is both a feasible and powerful strategy for developing more efficient nucleic acid-based therapies with the added benefit of allowing for non-invasive MR imaging of ODND therapeutic targeting and response.