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Immune recognition and uptake of nanoparticles remain the hot topic in nanomedicine research. Complement is the central player in the immune recognition of engineered nanoparticles. Here, we summarize the accumulated knowledge on the role of complement in the interactions of nanomaterials with blood phagocytes. We describe the interplay between surface properties, complement opsonization, and immune uptake, primarily of iron oxide nanoparticles. We discuss the rigor of the published research and further identify the following knowledge gaps: 1) the role of complement in the variability of uptake of nanomaterials in healthy and diseased subjects, and 2) modulation of complement interactions to improve the performance of nanomaterials. Addressing these gaps is critical to improving translational chances of nanomaterials for drug delivery and imaging applications., Competing Interests: Declaration of Competing Interest No conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Pluronic F127-stabilized non-lamellar liquid crystalline aqueous nanodispersions are promising injectable platforms for drug and contrast agent delivery. These nanodispersions, however, trigger complement activation in the human blood, where the extent of complement activation and opsonization processes may compromise their biological performance and safety. Here, we introduce a broad family of nanodispersions from glycerol monooleate (GMO) and oleic acid (OA) in different weight ratios, and stabilized with a plethora of nonionic methoxypoly(ethylene glycol) (mPEG)-lipids of different PEG chain length and variable lipid moiety (monounsaturated or saturated diglycerides or D-α-tocopheryl succinate). Through an integrated biophysical approach involving dynamic light scattering, synchrotron small-angle scattering, and cryo-transmission electron microscopy, we examine the impact of nonionic mPEG-lipid stabilization on size, internal self-assembled architecture, and gross morphological characteristics of nanodispersions. The results show how the nonionic mPEG-lipid type and concentration, and dependent on GMO/OA weight ratio, can variably modulate the internal architectures of nanoparticles. Assessment of complement profiling from selected nanodispersions with diverse structural heterogeneity further suggests a variable modulatory role for the lipid type of the nonionic mPEG-lipid in the extent of complement activation, which span from no activation to moderate to high levels. We comment on plausible mechanisms driving the observed complement activation variability and discuss the potential utility of these nanodispersions for future development of injectable nanopharmaceuticals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)