Author summary SARS-CoV-2 infection triggers the production of various antibodies, however, in in-vitro assays, some antibodies targeting the N-terminal domain (NTD) of the viral spike protein unexpec...

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The SARS-CoV-2 nucleocapsid (N) protein is essential for viral RNA packaging, replication, and immune modulation. Despite its central role, the mechanistic contributions of its individual domains, the N-terminal domain (NTD), C-terminal domain (CTD), and the intrinsically flexible linker (LINK), remain poorly defined, largely due to the proteins structural complexity. In this study, we developed a panel of twelve alpaca-derived nanobodies (VHHs) targeting the NTD, CTD, and LINK regions of N. Using ELISA and biolayer interferometry, we characterized their binding affinities, and we mapped their epitopes via hydrogen-deuterium exchange-mass spectrometry (HDX-MS) and structural modeling. When expressed intracellularly, these VHHs inhibited SARS-CoV-2 infection. In vitro, they disrupted phase separation of the N protein, a critical step in viral replication. Strikingly, VHHs targeting each domain independently blocked both phase condensation and viral replication, underscoring the functional importance of all three regions. These findings establish domain-specific VHHs as versatile tools for dissecting N biology, with promising therapeutic potential. ### Competing Interest Statement Timothy Bates and Fikadu Tafesse are co-founders of AlpaCure LLC. All other authors declare no competing interests. NIH National Institute of Allergy and Infectious Diseases (NIAID), R01AI141549, R01 AI152579, T32AI170496 Natural Science and Engineering Research Council of Canada (NSERC) MJ Murdock Foundation

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