Immunoglobulin deposition on biomolecule corona determines complement opsonisation efficiency of preclinical and clinical nanoparticles

Deposition of complement factors (opsonisation) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonisation of superparamagnetic iron oxide nanoworms (SPIO NWs) with the third complement protein (C3) was dependent on the biomolecule corona. Here we show that natural antibodies play a critical role in C3 opsonisation of SPIO NWs and a range of clinically approved nanopharmaceuticals. The dependency of C3 opsonisation on immunoglobulin binding is predominantly universal and is observed regardless of the complement activation pathway. Few surface-bound immunoglobulin molecules trigger complement activation and opsonisation. While the total amount of nanoparticle-absorbed protein does not determine C3 deposition efficiency, the biomolecule corona per se enhances immunoglobulin binding to all nanoparticle types. We therefore show that natural antibodies represent a link between biomolecule corona and C3 opsonisation, and may determine individual complement responses to nanomedicines.