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Sterilization of Drug‐Resistant Influenza Virus through Genetic Interference Inspired by Unnatural Amino Acid‐Engineered Particles

The frequent emergence of drug resistance during the treatment of influenza A virus (IAV) infections highlights a need for effective antiviral countermeasures. Here, this work presents an antiviral method that utilizes unnatural amino acid‐engineered drug‐resistant (UAA‐DR) virus generated through genetic code expansion to combat emerging drug‐resistant viruses through genomic segment reassortment to produce sterilized progenies due to artificial amber codons in the viral genome. This work validates in vitro that UAA‐DR can provide a broad‐spectrum antiviral strategy for several H1N1 strains, different DR‐IAV strains, multidrug‐resistant (MDR) strains, and even antigenically distant influenza strains (e.g., H3N2). Moreover, a minimum dose of neuraminidase (NA) inhibitors for influenza virus can further enhance the sterilizing effect when combating inhibitor‐resistant strains, partly due to the promoted superinfection of unnatural amino acid‐modified virus in cellular and animal models. The fact that the antiviral effect of UAA‐DR virus cannot be attributed to interferon stimulation and interferon stimulating genes is also investigated. It is anticipated that UAA‐engineered virus‐like particle can be extended to combat emerging drug‐resistant influenza virus and other segmented RNA viruses.