Notwithstanding rapid advances of nanotechnology in diagnostic imaging and drug delivery, the engineered nanocarriers still exhibit substantial lack of hemocompatibility. Thus, when injected systemically, nanoparticles are avidly recognized by blood leukocytes and platelets, but the mechanisms of immune recognition are not well understood and strategies to mitigate these phenomena remain underexplored. Using superparamagnetic
dextran iron oxide (
SPIO) nanoworms (NWs) we demonstrate an efficient and predominantly
complement-dependent uptake by mouse lymphocytes, neutrophils and monocytes from normal and
tumor bearing mice in vitro. Following
intravenous injection into wild type mice, blood leukocytes as well as platelets became magnetically labeled, while the labeling was decreased by 95% in
complement C3-deficient mice. Using blood cells from healthy and
cancer patient donors, we demonstrated that neutrophils, monocytes, lymphocytes and eosinophils took up
SPIO NWs, and the uptake was prevented by
EDTA (a general
complement inhibitor) and by antiproperdin antibody (an inhibitor of the alternative pathway of the
complement system). Cross-linking and hydrogelation of
SPIO NWs surface by
epichlorohydrin decreased C3 opsonization in mouse serum, and consequently reduced the uptake by mouse leukocytes by more than 70% in vivo. Remarkably, the cross-linked particles did not show a decrease in C3 opsonization in human serum, but showed a significant decrease (over 60%) of the uptake by human leukocytes. The residual uptake of cross-linked nanoparticles was completely blocked by
EDTA. These findings demonstrate species differences in
complement-mediated nanoparticle recognition and uptake by leukocytes, and further show that human hemocompatibility could be improved by inhibitors of
complement alternative pathway and by nanoparticle surface coating. These results provide important insights into the mechanisms of hemocompatibility of nanomedicines.