Conjugation chemistries are a major enabling technology for the development of drug delivery systems, from antibody-drug conjugates to antibody-targeted lipid nanoparticles inspired by the success of the COVID-19 vaccine. However, here it is shown that for antibody-targeted nanoparticles, the most popular conjugation chemistries directly participate in the activation of the complement cascade of plasma proteins. Their activation of complement leads to large changes in the biodistribution of nanoparticles (up to 140-fold increased uptake into phagocytes of the lungs) and multiple toxicities, including a 50% drop in platelet count. It is founded that the mechanism of complement activation varies dramatically between different conjugation chemistries. Dibenzocyclooctyne, a commonly used click-chemistry, caused aggregation of conjugated antibodies, but only on the surface of nanoparticles (not in bulk solution). By contrast, thiol-maleimide chemistry do not activate complement via its effects on antibodies, but rather because free maleimide bonded to albumin in plasma, and clustered albumin is then attacked by complement. Using these mechanistic insights, solutions are engineered that reduced the activation of complement for each class of conjugation chemistry. These results highlight that while conjugation chemistry is essential for the future of nanomedicine, it is not innocuous and must be designed with opsonins like complement in mind.