Impact of the protein corona on metal oxide nanoparticle-induced toxicity mechanisms

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Besides the prevalent use of nanoparticles (NPs) in industrial products, also their biomedical applications are expanding. Although both developments will result in an increasing exposure of humans to NPs, our current mechanistic knowledge of processes at the nano-bio interface is still fragmented. NPs adsorb biomolecules upon contact with all biological environments forming the so called NP-biomolecule corona. Importantly, we and others showed that particularly the protein corona critically impacts not only nanotoxicology but also the success and safety of nanobiomedical applications. Thus, biological systems are mostly not facing pristine manufactured but rather corona-coated transformed NPs. Moreover, the underlying molecular mechanisms how corona proteins affect the nano-bio interface are not yet resolved. We showed that focusing on highly controllable NP models combined with systematic analysis is key to correlate observed effects with distinct NP characteristics. Hence, we will investigate metal oxide NPs (MOx_NPs) not only representing an industrially and biomedical relevant category of NPs but also an excellent model system. Indeed the MOx_NPs physico-chemical characteristics. Hence, their controlled doping with other metals allows to control their reactivity and thus, to correlate reactivity with biological effects. However, the relevance of the protein corona was not studied so far. Based on our previous work we expect that the corona is also a key factor for MOx_NPs-triggered (adverse) biological effects by influencing oxidative stress, (subtoxic) signalling, cellular uptake, and intracellular dissolution processes. Consequently, combining controlled MOx_NPs synthesis and characterization with state-of-the-art analytical methods, such as multi-parametric high-content analysis, mass-spectrometry based proteomics together with (co-culture) in vitro exposure cell models, the scientific objectives of the project are: Aim 1. Analysing the impact of the biomolecule corona on the physico-chemical properties (size, surface charge, colloidal stability, aging) of MOx_NPs with incremental PdO-/Fe-dopings. Aim 2. Profiling of the MOx_NPs protein coronas by quantitative proteomics. Aim 3. Employing systematic high-content cell-based analysis to determine the impact of the protein corona on vitality, signaling, and oxidative stress responses in human exposure cell models. Aim 4. Bioinformatic correlation analysis and identification of protein corona signatures correlating with the MOx_NPs nano structure-activity relationships (nanoSARs). Aim 5. Experimentally identify key corona proteins causally involved in MOx_NPs-induced (patho)biological effects by fractionation and functional evaluation experiments. The generated knowledge will not only improve our understanding of basic processes at the nano-bio interface but may subsequent exploited to rationally design nanomaterials with improved efficacy, safety, and biocompatibility.