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Monoclonal anti‐SARS‐CoV‐2 immunoglobulins represent a treatment option for COVID‐19. However, their production in mammalian cells is not scalable to meet the global demand. Single‐domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. Using alpaca immune libraries against the receptor‐binding domain (RBD) of the SARS‐CoV‐2 Spike protein, we isolated 45 infection‐blocking VHH antibodies. These include nanobodies that can withstand 95°C. The most effective VHH antibody neutralizes SARS‐CoV‐2 at 17–50 pM concentration (0.2–0.7 µg per liter), binds the open and closed states of the Spike, and shows a tight RBD interaction in the X‐ray and cryo‐EM structures. The best VHH trimers neutralize even at 40 ng per liter. We constructed nanobody tandems and identified nanobody monomers that tolerate the K417N/T, E484K, N501Y, and L452R immune‐escape mutations found in the Alpha, Beta, Gamma, Epsilon, Iota, and Delta/Kappa lineages. We also demonstrate neutralization of the Beta strain at low‐picomolar VHH concentrations. We further discovered VHH antibodies that enforce native folding of the RBD in the E. coli cytosol, where its folding normally fails. Such "fold‐promoting" nanobodies may allow for simplified production of vaccines and their adaptation to viral escape‐mutations. SYNOPSIS: Effective treatment options for SARS‐CoV‐2 infections/COVID‐19 are still sparse. This study revealed highly potent therapeutic nanobodies/single‐domain (VHH) antibodies that neutralize SARS‐CoV‐2 and its emerging immune‐escape mutants. Alpaca immune libraries yielded 45 VHHs (of 22 sequence classes) that target two epitopes of the SARS‐CoV‐2 receptor‐binding domain (RBD) and block infection.The lead nanobody monomers are hyperthermostable, bind the RBD with low‐picomolar affinity and neutralize the virus at a concentration of 0.2–0.7 micrograms per liter (IC99+).Enhancement of the nanobodies' avidity by trimerization with the collagen XVIII NC1 domain yields neutralizers that block SARS‐CoV‐2 at concentrations as low as 40 nanograms per liter (IC99+).Clinical candidates include nanobody trimers, tandem fusions and monomers that bind the major SARS‐CoV‐2 immune‐escape mutants with high affinity and neutralize, e.g., the Beta/B.1.351 variant."Fold‐promoting" nanobodies assist de novo protein folding in the E. coli cytosol, as demonstrated with nanobody⋅RBD complexes. [ABSTRACT FROM AUTHOR]