<i>In chemico</i> categorization of magnetite-, hydroxyapatite-, and Ag-derived hybrid nanobiomaterials based on the surface oxidative reactivity: implications of doping and coating

<i>In chemico</i> tests are important tools that complement <i>in silico</i>, <i>in vitro</i> and <i>in vivo</i> approaches to predict the toxicological impact of nanomaterials (NMs). Here, we apply a recently proposed <i>in chemico</i> methodology, based on the evaluation of the number, nature and properties of reactive surface sites of NMs, to a series of magnetite-, hydroxyapatite- and silver-based hybrid nanobiomaterials (NBMs). The properties of the NBMs were examined using methanol chemisorption followed by temperature-programmed surface reaction (MeOH-TPSR), dithiothreitol (DTT) oxidation, cyclic voltammetry in biologically relevant media, and electron paramagnetic resonance (EPR) spectroscopy in a series of relevant media as a spin trap. The resulting data were critically compared and correlated with the available <i>in vitro</i> data of the NBMs' hazard. Our findings reveal significant differences in the oxidative potential of these hybrid NBMs. Iron (Fe) doping in hydroxyapatite (HA) introduced new redox-active surface sites, leading to increased oxidative reactivity <i>via</i> ROS-independent mechanisms, as evidenced by higher DTT depletion and Fenton-like activity compared to HA. Conversely, titanium (Ti) doping modified HA's surface by introducing acidic active sites, reducing its oxidative capacity. Coating Fe₃O₄ with poly(ethylene glycol)-poly(lactic-<i>co</i>-glycolic) acid (PEG-PLGA) enhanced the oxidative reactivity without ROS generation, suggesting a surface-driven process. In contrast, hydroxyethyl cellulose (HEC) coating significantly reduced the high reactivity of uncoated silver (Ag). This study underscores the importance of determining the NBMs' reactivity profile for safe biomedical use, highlighting how specific coatings and dopants can transform oxidative surface properties.