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Previously, an anti\u2010SARS\u2010CoV\u20102 nanobody, Nanosota\u20103A, that neutralizes the infection of live Omicron BA.1 with picomolar potency, is identified. Herein, Nanosota\u20103A is fused with the crystallizable fragment (Fc) domain of human IgG1 that contains M252Y\/S254T\/T256E (YTE) substitutions, named Nanosota\u20103A\u2010Fc\u2010YTE. Compared to Nanosota\u20103A\u2010Fc, Nanosota\u20103A\u2010Fc\u2010YTE exhibits identical binding to the SARS\u2010CoV\u20102 spike protein yet displays eightfold higher binding affinity for human neonatal Fc receptor (hFcRn) at pH 6.0. In hFcRn transgenic mice, the half\u2010life of Nanosota\u20103A\u2010Fc and Nanosota\u20103A\u2010Fc\u2010YTE is 5.1\u2009days and 24.8\u2009days, respectively. The mice are challenged with intranasal exposure of Omicron B.1.1.529 virus 55\u2009days after a single dose of Nanosota\u20103A fusions (20\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>) is administered. Compared to the untreated controls, the lung viral titers in mice receiving Nanosota\u20103A\u2010Fc\u2010YTE are reduced by 104.7\u2010fold (<jats:italic>p<\/jats:italic>\u2009=\u20090.007) with 50% of the mice free of detectable virus. By contrast, Nanosota\u20103A\u2010Fc\u2010treated mice show only 3.5\u2010fold reduction in the viral titers (<jats:italic>p<\/jats:italic>\u2009=\u20090.41). The durable protection conferred by a single dose of Nanosota\u20103A\u2010Fc\u2010YTE administered nearly 2\u2009months prior to the virus exposure demonstrates the promise of long\u2010circulating nanobodies as powerful prophylactics against SARS\u2010CoV\u20102.<\/jats:p>","DOI":"10.1002\/anbr.202400214","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T13:39:13Z","timestamp":1751031553000},"source":"Crossref","is-referenced-by-count":2,"title":["Long\u2010Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection"],"prefix":"10.1002","volume":"5","author":[{"given":"Geetha Jyothi","family":"Vaskuri","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Tennessee Health Science Center  Memphis TN 38163 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