Mechano‐Locking Strategy for Broad‐Spectrum SARS‐CoV‐2 Neutralization

Viral entry into host cells is typically initiated by interactions between viral surface proteins and host cell receptors. Conventional neutralization strategies aim to disrupt these interactions but often lose effectiveness against rapidly mutating viral strains. This challenge extends beyond SARS‐CoV‐2 to other viruses such as HIV and influenza. To overcome this limitation, a novel mechano‐locking strategy is proposed, using SARS‐CoV‐2 as a model system, in which bispecific antibodies (bsAbs) lock the spike protein in its prefusion conformation by preventing force‐induced conformational changes. These bsAbs demonstrate broad‐spectrum neutralization efficacy against multiple SARS‐CoV‐2 variants in pseudoviral assays. Single‐molecule magnetic tweezers experiments further reveal that these bsAbs significantly raise the mechanical force threshold required for S1–S2 dissociation, thereby enhancing spike protein mechano‐stability. This stabilization mechanism offers a mutation‐resistant 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.