A highly potent nanobody-based bispecific therapeutic provides broad-spectrum protection against ebolavirus

The highly lethal Ebola virus species—Zaire (EBOV), Sudan (SUDV), and Bundibugyo (BDBV)—pose persistent threats to global health. Current antibody therapies target EBOV but lack broad neutralization across ebolaviruses. Recent pan-ebolavirus strategies rely on antibody cocktails. Here, we identified two camelid-derived nanobodies (1A10 and BA2) that neutralize EBOV, SUDV, and BDBV in vitro and protect female rodents against these pathogens. High-resolution cryo-EM structures of their GP complexes showed that 1A10 and BA2 bind conserved but non-overlapping epitopes near the GP1 base and GP2’s internal fusion loop (IFL), and biochemical analyses revealed their distinct neutralization mechanisms. To further improve efficacy, we engineered a bispecific antibody (BA2-1A10) via GS linker-mediated IgG-Fc fusion, which provided highly potent protection against all three viruses in female rodents model and positions it as a strong broad-spectrum anti-ebolavirus candidate. Our work demonstrates a structure-guided bispecific nanobody strategy for pan-ebolavirus therapy and highlights compact antibodies for next-generation antivirals. Current antiviral treatment approaches target specific Ebola virus species. Here, the authors develop bispecific antibodies with pan-ebolavirus neutralization capacity, structurally resolve the epitope and neutralization mode and show potent protection in a rodent model.