Surface Chemistry Governs Early Redox and Cytokine Responses to Superparamagnetic Iron Oxide Nanoparticles Across Hepatic-Relevant Cell Models.

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) are increasingly utilised in biomedical and nanomedicine applications, raising important questions regarding early interactions with hepatic cellular systems. This study investigated how surface chemistry influences the biological behaviour of SPIONs across hepatic-relevant cell models through integrated physicochemical characterisation and response screening. Carboxyl (CAR), amine (AMI), and polyethylene glycol (PEG)-coated SPIONs were characterised in biologically relevant media, revealing coating-dependent agglomeration. SPION exposure (2-24h) was conducted in THP-1 (macrophage-like), Hep G2 (hepatocyte), EA.hy926 (endothelial), and HMC-1.1 (mast cell) models to assess cytotoxicity, redox balance and inflammatory signalling. SPION-induced reactive oxygen species generation and reduced glutathione depletion occurred in a coating- and cell-type-dependent manner, with THP-1 cells showing the greatest sensitivity. Cytokine profiling revealed different responses across models. THP-1 cells demonstrated pronounced pro-inflammatory activation, including increased IL-8, IL-1β and IL-18 secretion, with PEG-SPIONs driving the strongest effects. Conversely, Hep G2 cells exhibited a largely suppressive phenotype characterised by reduced cytokine secretion, while EA.hy926 and HMC-1.1 cells displayed temporally and ligand-dependent responses. Across models, biological responses were associated with nanoparticle dispersion behaviour, supporting agglomeration as an important determinant of early nanoparticle-cell interactions. he association between altered dispersion, redox perturbation and inflammatory responses supports a model in which SPION surface chemistry influences nanoparticle behaviour in biological media, thereby modulating oxidative stress and inflammatory signalling in a cell-dependent manner. Notably, these responses occurred in the absence of overt cytotoxicity, highlighting early perturbations in redox and inflammatory signalling as sensitive indicators of nanoparticle biological activity that may precede overt cellular damage.

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