objective: Inflammatory bowel diseases are highly debilitating conditions that require constant monitoring and life-long medication. Current treatments are focused on systemic administration of immunomodulatory drugs, but they have a broad range of undesirable side-effects. The RNA interference is a highly specific endogenous mechanism that regulates the expression of the gene at the transcript level, which can be repurposed using exogenous short interfering RNA (siRNA) in order to repress the target gene's expression. While siRNA therapeutics can offer an alternative to existing therapies, with a high specificity critical for chronically administrated drugs, evidence of their potency compared to chemical kinase inhibitors used in clinics is still lacking in alleviating an adverse inflammatory response. methods: We provide a framework to select highly specific siRNA, with a focus on two kinases strongly involved in pro-inflammatory diseases, namely JAK1 and JAK3. Using western-blot, RTqPCR and large scale analysis, we assessed the specificity profile of these siRNA drugs and compared their efficacy to the most recent and promising kinase inhibitors for Janus kinases (Jakinibs), Tofacitinib and Filgotinib. results: siRNA drugs can reach higher efficiency and selectivity at lower doses (5 pM versus 1 μM) than Jakinibs. Moreover, JAK silencing was lasting up to 11 days, even with 6h pulse transfection. conclusions: The siRNA-based drugs developed hold the potential to develop more potent therapeutics for chronic inflammatory diseases.