biostudies-literatureChang YCMinistry of Science and Technology, Taiwane15298https://www.ebi.ac.uk/biostudies/studies/S-EPMC8988202biostudies-literatureUnknown14(4)The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants has altered the trajectory of the COVID-19 pandemic and raised some uncertainty on the long-term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS-CoV-2 variants is imperative. We, here, have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS-CoV-2 variants and is capable of inhibiting dominant strains, including Alpha, Delta, Gamma, and Epsilon, at picomolar ranges of IC₅₀ in vitro. Moreover, C6G25S could completely inhibit the production of infectious virions in lungs by prophylactic treatment, and decrease 96.2% of virions by cotreatment in K18-hACE2-transgenic mice, accompanied by a significant prevention of virus-associatEMBO molecular medicineA siRNA targets and inhibits a broad range of SARS-CoV-2 infections including Delta variant.PMC8988202MOST 109‐2124‐M‐002‐012MOST‐110‐2740‐B‐002‐006MOST 110‐0210‐01‐22‐02MOST 109‐0210‐01‐18‐02MOST109‐2327‐B‐002‐009Chang JYHsu SCFang JTTsai YMChou YLChen YFChang FYChao TLKao HCChang TYChang SYYang CFLu HYChang YCChou HWWeng RSChin YFTu QWHuang KYYang CCLiu PCLee TYIeong SMYang PCfalseA siRNA targets and inhibits a broad range of SARS-CoV-2 infections including Delta variant.The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants has altered the trajectory of the COVID-19 pandemic and raised some uncertainty on the long-term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS-CoV-2 variants is imperative. We, here, have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS-CoV-2 variants and is capable of inhibiting dominant strains, including Alpha, Delta, Gamma, and Epsilon, at picomolar ranges of IC₅₀ in vitro. Moreover, C6G25S could completely inhibit the production of infectious virions in lungs by prophylactic treatment, and decrease 96.2% of virions by cotreatment in K18-hACE2-transgenic mice, accompanied by a significant prevention of virus-associat2022-01-01T00:00:00Z2022 Apr2026-05-10T00:56:51.441Z2025-04-07T01:53:12.306ZS-EPMC89882023513802810.15252/emmm.202115298