Toll-Like Receptor 7 (TLR7), which is encoded on ChrX, is a critical innate immune sensor of RNA. Recently, a direct link was established of TLR7 role in the development of systemic lupus erythematosus (SLE) in patients. As such, it was found that rare mutations in TLR7 governed hyperactivity and are sufficient to promote production of autoantibodies and subsequently contributed to the development of (SLE). This suggested TLR7 as a novel target for the treatment of SLE [Brown et al., Nature 2022]. However, there are no TLR7 inhibitors currently approved for use in humans. Our team recently reported that 2’Omethyl- modified 20nt long RNA/DNA oligonucleotides broadly inhibited TLR7 sensing, suggesting that such synthetic nucleic acids could be designed to limit TLR7-driven autoimmunity [Alharbi et al., Nucleic Acids Res. 2020]. Here, we discovered that selected motifs, with as few as 3 bases, control the strong antagonistic effect of oligonucleotides on TLR7 sensing, including that of the disease promoted by TLR7 mutants. Critically, we demonstrated that selected 3nt oligonucleotides phenocopied the inhibitory effects of longer oligonucleotides on TLR7 sensing. Importantly, our extensive analyses of chemical modifications confirmed that TLR7 inhibition is not limited to 2’Omethyl sequences and is broadly observed across synthetic 20nt long oligonucleotides, dependent on selected motifs. Relying on structural modelling we are now investigating the design of hyper-suppressive therapeutic 3nt oligonucleotides to help dampen aberrant TLR7 signalling in SLE and other TLR7-driven diseases.