<p>Plasma protein adsorption on Fe₃O₄-PEG nanoparticles activates the complement system and induces an inflammatory response</p>

Abstract

Background: Understanding of iron oxide nanoparticles (IONP) interaction with the body milieu is crucial to guarantee their efficiency and biocompatibility in nanomedicine. Polymer coating to IONP, with polyethyleneglycol (PEG) and polyvinylpyrrolidone (PVP), is an accepted strategy to prevent toxicity and excessive protein binding. Aim: The aim of this study was to investigate the feature of IONP adsorption of complement proteins, their activation and consequent inflammatory response as a strategy to further elucidate their biocompatibility. Methods: Three types of IONP with different surface characteristics were used: bare (IONPbare), coated with PVP (IONP-PVP) and PEG-coated (IONP-PEG). IONPs were incubated with human plasma and adsorbed proteins were identified. BALB/c mice were intravenously exposed to IONP to evaluate complement activation and proinflammatory response. Results: Protein corona fingerprinting showed that PEG surface around IONP promoted a selective adsorption of complement recognition molecules which would be responsible for the complement system activation. Furthermore, IONP-PEG activated in vitro, the complement system and induced a substantial increment of C3a and C4a anaphylatoxins while IONP-bare and IONP-PVP did not. In vivo IONP-PEG induced an increment in complement activation markers (C5a and C5b-9), and proinflammatory cytokines (IL-1β, IL-6, TNF-α). Conclusion: The engineering of nanoparticles must incorporate the association between complement proteins and nanomedicines, which will regulate the immunostimulatory effects through a selective adsorption of plasma proteins and will enable a safer application of IONP in human therapy.

<p>Effects of PEGylation on capture of dextran-coated magnetic nanoparticles in microcirculation</p>

“…The enhanced capture of smaller PEG(+) MNPs may be attributed to the PEG–plasma protein interaction and then agglomerate formation, resulting in an increased hydrodynamic diameter of MNPs. It has been recently demonstrated that plasma protein adsorption of PEG(+) MNPs, but not bare MNPs, triggers complement activation,56 which may consequently alter protein corona composition, physical characteristics and particle behaviors in circulation. For larger MNPs, PEGylation may reduce particle–particle interaction induced by magnetic moment generation in magnetic field, and thus enhance MNP escape, allowing dynamic retention of MNPs in vivo.…”

In vivo Protein Corona Formation: Characterizations, Effects on Engineered Nanoparticles’ Biobehaviors, and Applications

“…Thus, immunotoxicity is one of the main toxicity of ENPs induced by PC in body. For example, PEG-coated iron oxide NPs (IONP-PEG) can trigger complement activation and induces an inflammatory response (increased in proinflammatory cytokines such as IL-1β, IL-6, and TNF-α) ( Rivera et al, 2019 ). Magnetic nanoparticle (MNP)-infiltrated bone regeneration scaffolds could also adsorb inflammatory related protein such as alpha-2-HS-glycoprotein, haptoglobin, and complement components, which can activate the immune system ( Figure 2A ; Zhu et al, 2019 ).…”

The Intrinsic Biological Identities of Iron Oxide Nanoparticles and Their Coatings: Unexplored Territory for Combinatorial Therapies

“…The biomolecular corona must be taken into account when considering the intrinsic biological effects that IONPs can produce. Indeed, Escamilla-Rivera et al found that PEG-coated IONPs absorb a wide variety of complement recognition proteins when incubated with human serum, leading to complement activation when injected in mice [ 95 ]. Similarly, Zhu et al demonstrated that the addition of IONPs to the hyaluronic acid (HA) scaffold enhances osteogenesis in vivo, most likely mediated by a dynamic formation of a protein corona enriched in complement-, wound healing-, and inflammatory-related factors [ 96 ].…”