This study identifies and optimizes fully chemically modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and multiple other species. The researchers validated these siRNAs in silencing JAK1 in cell lines and skin tissues of various species, including humans, non-human primates (NHPs), rodents, and pigs. JAK1 is a key regulator of inflammatory cytokine signaling pathways, and its dysregulation is implicated in immune disorders. The study highlights the potential of these siRNAs for evaluating the modulation of JAK1 in animal models of human inflammatory skin diseases. The optimized siRNAs, particularly si860, showed significant silencing of JAK1 in multiple species, suggesting their utility in preclinical development and clinical translation. The findings also demonstrate the importance of target site homology across species for cross-species activity and the potential for further chemical engineering to enhance their therapeutic potential.This study identifies and optimizes fully chemically modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and multiple other species. The researchers validated these siRNAs in silencing JAK1 in cell lines and skin tissues of various species, including humans, non-human primates (NHPs), rodents, and pigs. JAK1 is a key regulator of inflammatory cytokine signaling pathways, and its dysregulation is implicated in immune disorders. The study highlights the potential of these siRNAs for evaluating the modulation of JAK1 in animal models of human inflammatory skin diseases. The optimized siRNAs, particularly si860, showed significant silencing of JAK1 in multiple species, suggesting their utility in preclinical development and clinical translation. The findings also demonstrate the importance of target site homology across species for cross-species activity and the potential for further chemical engineering to enhance their therapeutic potential.