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Globally, there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss and substantially reduces viral burdens in both lower and upper airways compared to control. Aerosol delivery of PiN-21 facilitates deposition throughout the respiratory tract and dose minimization to 0.2 mg/kg. Inhalation treatment quickly reverses animals’ weight loss after infection, decreases lung viral titers by 6 logs leading to drastically mitigated lung pathology, and prevents viral pneumonia. Combined with the marked stability and low production cost, this innovative therapy may provide a convenient and cos

United statesSakura finetekAkoya biosciencesEconomic developmentAccreditation of laboratory animal careCommonwealth of pennsylvania department communityHenryl hillman foundationUniversity of pittsburghRichard king mellon foundationVaccine researchAssociation for assessmentLaboratory animalsNational institutes of healthUniversity of pittsburgh centerUniversity of pittsburgh institutional animal carePublic health services policy on humane care