Originally conceived as a method to silence transcription/ translation of nascent RNA, nucleic acids aimed at downregulating gene expression have been shown to act at multiple levels. Some of the intriguing features of these gene-silencing nucleic acids include activation of molecular signals in immune cells which confer tolerogenic properties. We have discovered a method to induce stable tolerogenic ability to dendritic cells ex vivo using a mixture of phosphorothioate- modified antisense DNA targeting the primary transcripts of CD40, CD80 and CD86. Autologous human dendritic cells generated in the presence of these oligonucleotides prevent and reverse type 1 diabetes (T1D) in the non-obese diabetic (NOD) strain mouse model of the human disease, and have been shown to be safe in established diabetic human patients. Even though this ex vivo approach is clinically feasible, we have gone beyond a cell therapy approach to develop a “population-targeting” microsphere formulation of the three antisense oligonucleotides. Effectively, such a product could constitute an “off-the-shelf” vaccine. In this paper, we describe the progress made in developing this approach, as well as providing some insight into potential molecular mechanisms of action.