The mechanism of RNA interference (RNAi) is a highly conserved process of post-transcriptional gene regulation, mediated by short interfering RNA (siRNA) molecules. Since the conceptualisation of targeted gene therapy, siRNA has appeared as an extremely attractive therapeutic candidate against a range of diseases, including viral infections. However, the translation of siRNA into a clinical therapy has been delayed by issues surrounding the delivery of siRNA to target cells. To overcome these obstacles, extensive efforts have been made to develop efficient delivery vehicles that protect and facilitate siRNA delivery in vivo. One promising delivery system are precision engineered synthetic polymers, synthesised by Reversible Addition Fragmentation chain Transfer (RAFT) mediated free radical polymerization. Here, we specifically aim to assess the efficiency of intranasal delivery of the siRNA using two RAFT polymer delivery vehicles in order to protect against respiratory viruses, like influenza. From our in vitro analyses, two candidate polymers have emerged; a biodegradable linear cholesterol-containing polymer and a cationic ‘Mikto star’ polymer. Both of these polymers have demonstrated high levels of siRNA transfection and corresponding target mRNA attenuation, good siRNA binding and satisfactory serum stability in cell culture models. We have now advanced these two polymer candidates to in vivo testing in mice to assess whether they can efficiently deliver siRNA molecules to the lung in order to protect mice from an influenza challenge. Results from these experiments show that delivery of siRNA with the mikto star polymer has few side effects and is capable of attenuating influenza infection. We are now well positioned to further our in vivo studies and advance our research towards functional animal studies and pre-clinical trials.