Epigenetic changes, including hypermethylation of DNA, are fundamental to progression and maintenance of epilepsy. Using silk-based brain implants engineered to release adenosine we demonstrated that reversal of epigenetic changes prevents epileptogenesis. We identified a novel mechanism by which adenosine reduces DNA methylation in the brain and translated those findings into a new therapeutic strategy biodegradable silk-based brain implants to prevent epileptogenesis long term. These findings constitute a novel scientific advance with direct clinical implications. Specifically, using bioengineered silk based brain implants we demonstrated that transient delivery of a defined focal dose of adenosine to epileptic rats can reverse pathological DNA hypermethylation. Further, we showed that this treatment can prevent epileptogenesis as assessed by the analysis of two independent outcome parametersseizures and mossy fiber sprouting. To our knowledge this is the first study where a robust antiepileptogenic effect has been demonstrated after the onset of epilepsy. Adenosine and silk are FDA approved thus our findings have direct translational value. In summary, we demonstrated that DNA methylation changes are integral to initiation and progression of epilepsy these epigenetic changes are modulated by adenosine, which is dysregulated in epilepsy focal transient silk-based adenosine augmentation reduces epilepsy associated DNA hypermethylation and halts disease progression.