Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo

Abstract

When nanoparticles are intravenously injected into the body, complement proteins deposit on the surface of nanoparticles in a process called opsonization. These proteins prime the particle for removal by immune cells and may contribute toward infusion-related adverse effects such as allergic responses. The ways complement proteins assemble on nanoparticles have remained unclear. Here, we show that dextran-coated superparamagnetic iron oxide core-shell nanoworms incubated in human serum and plasma are rapidly opsonized with the third complement component (C3) via the alternative pathway. Serum and plasma proteins bound to the nanoworms are mostly intercalated into the nanoworm shell. We show that C3 covalently binds to these absorbed proteins rather than the dextran shell and the protein-bound C3 undergoes dynamic exchange in vitro. Surface-bound proteins accelerate the assembly of the complement components of the alternative pathway on the nanoworm surface. When nanoworms pre-coated with human plasma were injected into mice, C3 and other adsorbed proteins undergo rapid loss. Our results provide important insight into dynamics of protein adsorption and complement opsonization of nanomedicines.

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population

“…We prepared SPIO NWs of two different sizes by varying the ratio between dextran and iron salts during the precipitation reaction as described previously. 25–28 A higher dextran-to-Fe ratio results in smaller NWs. 26 Transmission electron microscopy showed worm-like polycrystalline Fe 3 O 4 core ( Figure 1A,B).…”

“…LipoDox also showed low number of C3 per particle despite having much-larger diameters than Feraheme, most likely due to the PEGylated coating. For simplicity, the protein corona, which is critical for complement binding and activation, 11 is not shown here.…”

Effects of engineered nanoparticles on the innate immune system

“…The protein corona accelerates the assembly of complement components on the NP surface in vitro, however C3 and other absorbed proteins were rapidly shed from the surface once the NPs were injected to mice. The exchangeable nature of the protein corona can lead to continuous shedding of the complement factors and re-opsonization in vivo [51]. Based on the composition of the protein corona, Chan et al developed a quantitative model that uses a serum protein corona “fingerprint” to predict the cell association of 105 surface-modified AuNPs, with the larger goal of establishing predictive models for the design of NPs [52].…”

Interaction of extremophilic archaeal viruses with human and mouse complement system and viral biodistribution in mice

“…Superparamagnetic iron oxide (SPIO) nanoworms of 110 nm in size was prepared and characterized as described earlier (Chen et al, 2017). In some experiments, viral particles or SPIO nanoworms (1 × 10 13 SMV1 or SPIO nanoworms/mL) were incubated with mouse serum or human serum (volume ratio 1:3) for 30 min at 37 °C.…”

“…The integrated dot intensity in the scanned images was determined from 16-bit grayscale images using ImageJ software and plotted using Prism 6 software (GraphPad Software, Inc., CA, USA). The integrated density of fB, fH and C3 was determined by dot blot immunoassay against the standard dilutions of purified fB, fH and iC3b, respectively as described earlier (Chen et al, 2017; Wang et al, 2017). …”