A 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 IC 50 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‐associated extensive pulmonary alveolar damage, vascular thrombi, and immune cell infiltrations. Our data suggest that C6G25S provides an alternative and effective approach to combating the COVID‐19 pandemic. Synopsis C6G25S is a fully modified siRNA specifically targeting the highly‐conserve region of SARS‐CoV‐2 genome. It has been developed as an inhalable and broad‐spectrum therapeutic that is highly stable and effective via direct respiratory administration. A broadly active siRNA covers 99.8% of SARS‐CoV‐2 variants, including highly infective Delta and Omicron. C6G25S completely inhibited the Delta variant in lungs of infected mice by prophylactic treatment and decreased 93% of virions by co‐treatment. First study that use fully modified siRNA for inhalation and achieved promising therapeutic effect without a special delivery system. C6G25S is a safe, effective, and feasible therapeutic approach that could reach the market in a short time. Graphical Abstract C6G25S is a fully modified siRNA specifically targeting the highly‐conserve region of SARS‐CoV‐2 genome. It has been developed as an inhalable and broad‐spectrum therapeutic that is highly stable and effective via direct respiratory administration.