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The immune system eliminates pathogen intruders such as viruses and bacteria. To recruit immune effectors to virus-infected cells, we conjugated a small molecule, the influenza neuraminidase inhibitor zanamivir, to a nanobody that recognizes the kappa light chains of mouse immunoglobulins. This adduct was designed to achieve half-life extension of zanamivir through complex formation with the much-larger immunoglobulins in the circulation. The zanamivir moiety targets the adduct to virus-infected cells, whereas the anti-kappa component simultaneously delivers polyclonal immunoglobulins of indeterminate specificity and all isotypes. Activation of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity promoted elimination of influenza neuraminidase-positive cells. A single dose of the conjugate protected mice against influenza A or B viruses and was effective even when given several days after infection with a lethal dose of virus. In the absence of circulating immunoglobulins, we observed no in vivo protection from the adduct. The type of conjugates described here may thus find application for both anti-influenza prophylaxis and therapy. Editor's summary: Antibodies not only directly neutralize their targets, but also possess Fc-mediated effector functions, including the ability to trigger complement-mediated and antibody-dependent cellular cytoxicity. To direct these responses against influenza virus-infected cells, Liu et al. engineered a conjugate composed of an anti-mouse kappa light chain nanobody (VHHkappa) linked to the neuraminidase inhibitor zanamivir. VHHkappa-zanamivir was capable of binding polyclonal immunoglobulins and initiating Fc-mediated effector functions against virus-infected cells. Mice given a single dose of VHHkappa-zanamivir were protected against lethal infections with both influenza A and B strains, and treatment could be delayed up to 2 days post-infection. Zanamavir could be exchanged for an influenza virus-specific nanobody, a conjugate that provided similar protection, thus demonstrating the versatility of this approach and the potential for application to other pathogens.–Claire Olingy [ABSTRACT FROM AUTHOR]