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Conventional neutralization strategies aim to disrupt these interactions but often lose effectiveness against rapidly mutating viral strains. This challenge extends beyond SARS\u2010CoV\u20102 to other viruses such as HIV and influenza. To overcome this limitation, a novel mechano\u2010locking strategy is proposed, using SARS\u2010CoV\u20102 as a model system, in which bispecific antibodies (bsAbs) lock the spike protein in its prefusion conformation by preventing force\u2010induced conformational changes. These bsAbs demonstrate broad\u2010spectrum neutralization efficacy against multiple SARS\u2010CoV\u20102 variants in pseudoviral assays. Single\u2010molecule magnetic tweezers experiments further reveal that these bsAbs significantly raise the mechanical force threshold required for S1\u2013S2 dissociation, thereby enhancing spike protein mechano\u2010stability. This stabilization mechanism offers a mutation\u2010resistant approach to neutralization and introduces a new design paradigm for antiviral therapeutics. These findings establish a mechanistically driven framework for developing biomechanically enhanced strategies potentially applicable to a wide range of mechanically activated enveloped viruses.<\/jats:p>","DOI":"10.1002\/smll.202505582","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T08:40:39Z","timestamp":1759826439000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechano\u2010Locking Strategy for Broad\u2010Spectrum SARS\u2010CoV\u20102 Neutralization"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3380-0197","authenticated-orcid":false,"given":"Yang","family":"Ye","sequence":"first","affiliation":[{"name":"Kidney Disease Center of the First Affiliated Hospital and Department of Cell Biology Zhejiang University School of Medicine  Hangzhou Zhejiang 310058 China"},{"name":"Department of Cardiology of the Second Affiliated Hospital and 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