Does Biofunctionalization Make ZnO and TiO2 Nanoparticles Safer? A Critical Review of Their Changing Toxicological Identity

ZnO and TiO2 nanoparticles are increasingly biofunctionalized to improve stability, biological recognition, targeting, and compatibility. However, whether biofunctionalization inherently makes these nanoparticles safer remains unresolved. Rather than cataloguing biofunctionalization strategies, this critical review evaluates whether toxicological changes can be attributed specifically to deliberate biomolecular surface modification and whether any resulting safety advantage persists during exposure-relevant transformations. A structured literature search identified 60 publications for critical synthesis, including 10 comparative studies providing direct evidence on toxicological changes attributable to deliberate biofunctionalization. The available evidence does not support a uniform toxicity-reducing effect. Depending on the nanoparticle-biointerface combination and exposure context, biofunctionalization can reduce toxicity, produce coating-dependent changes, increase biological accessibility, or redirect reactivity toward selected biological targets. These outcomes arise from changes in surface charge, aggregation, colloidal stability, cellular interactions, and biointerface evolution and are material-specific: ZnO additionally requires consideration of dissolution and Zn2+ release, whereas TiO2 behavior is more strongly influenced by particulate persistence and surface-mediated reactivity. We therefore conceptualize toxicological identity as an evolving, exposure-dependent profile rather than an intrinsic material property. Within a safe-by-design framework, biofunctionalization is advantageous only when it reduces non-target toxicity, preserves or improves the intended function, and maintains this advantage after exposure-relevant transformations.