Medical Gas Plasma Inactivates Adenoviruses via Capsid Oxidation

ABSTRACT Pandemics threaten societies, driving the need for new therapeutics. Medical gas plasma, a partially ionized gas, has been proposed as an antiviral agent, but its mechanisms of action are elusive. We employed a certified argon plasma jet and dynamic infection monitoring. Gas plasma exposure reduced adenovirus infectivity in lung cells in treatment time‐dependently, with 90s yielding infectivity losses of 96%. The antioxidants N‑acetylcysteine and tyrosine, and the nitric oxide scavenger carboxy‑PTIO, abrogated gas plasma‐mediated virus inactivation, implicating hydroxyl radicals and peroxynitrite chemistry (involving superoxide and nitric oxide) as key antiviral gas plasma agents. These did not induce virus DNA fragmentation or cross‐linking but morphological and virus size alterations (16.5% decrease). High‐resolution mass spectrometry identified oxidative hotspots on critical histidine and cysteine residues of penton, hexon, and fiber proteins, which are involved in cellular entry and stability. The dominant reactive pathways include oxidative and nitrosative chemistry caused by reactive oxygen and nitrogen species (e.g., •OH, 1O ₂ , O ₃ , H ₂ O ₂ , O ₂ ⁻ •, NO, and ONOO ⁻ ) generated by gas plasma, which lead to viral protein oxidation, lysis, and nucleic acid base modifications. Together, these findings delineate the mechanisms of gas plasma‐mediated viral inactivation and support its translational implementation.