Engineered Nanobodies Elicit Durable and Robust Bi‐Therapeutic Efficacy Toward Virus and Tumors

Abstract Nanobodies (Nbs) are one of the most promising therapeutics for overcoming immune escape in various diseases, including SARS‐CoV‐2 infection and cancers. However, the small sizes of nanobodies make them prone to renal clearance, thus decreasing circulation half‐life and hindering therapeutic efficacy. Traditional modification technologies, i.e., biotinylation and Fc‐fusion, aim to enhance nanobody pharmacokinetics, but they may introduce heterogeneous products with impaired functions and potentially affect binding to the Fc receptor. Here, a versatile nanobody engineering strategy is presented via molecular modification mediated by an intrinsically disordered protein. The engineered nanobody nano‐formulations retain their high‐affinity binding to the spike protein receptor binding domain and possess submicromolar levels of half‐maximal inhibitory concentration (IC 50 ) against the pseudotyped SARS‐CoV‐2 variants, comparable to the unmodified nanobodies. Notably, the nano‐formulations show elongated half‐lives that are up to ≈15 times higher than those of original nanobodies and superior to other reported modified nanobodies. Furthermore, the in vivo therapeutic efficacy of such nano‐formulation toward breast cancer is significantly enhanced. Therefore, this nanobody engineering strategy offers a convenient and broadly applicable solution to address the suboptimal in vivo performance of nanobodies, holding substantial promise for effectively combating treatment‐tolerant cancers and future pandemics.