Nucleic acid-based therapeutics have emerged and represent today, key targets in a wide range of diseases. Since natural oligonucleotides (ONs) are rapidly metabolized in biological media by nucleases and suffer from a poor cellular uptake, several chemical modifications were envisaged and led to the conception of ON analogs with good biological activities. However, in spite of the large number of ONs that are currently under clinical trials, the FDA approved only few of them. Thus, new series still deserve to be discovered regarding the high potential of ON-based therapeutics and the growing economical market of this field. Our project deals with the design and synthesis of new ON series that would be able to counteract the main limitations of current therapeutic ONs. In front of the importance of the fluorine atom in medicinal chemistry, we will be particularly interested in the preparation of fluorinated nucleic acids that have been less explored nowadays. Indeed, several organofluorinated groups will be introduced onto the 2’-position of nucleosides to increase both the thermal stability of RNA duplex, resistance towards nucleases as well as cellular uptake. To access to these target molecules, automated solid-phase phosphoramidite-based ON synthesis will be privileged. Indeed, new synthetic methodologies based on ionic and radical approaches will be first developed to synthesize the different fluorinated phosphoramidites in each nucleobase series (A, C, G, U). These laters will be then incorporated in various model sequences (siRNA, miRNA) to study their physico-chemical and biological properties.