The effects of nanoplastics on toxicity of metals and metal nanoparticles: molecular mechanisms and health effects

The objective of the present review is to discuss the effects and the underlying molecular mechanisms of co-exposure to nanoplastics (NPls) and metals, with a special focus on the difference between NPls and microplastics (MPls) in modulating metal toxicity. Findings from cellular models and in vivo studies with laboratory rodents, fish, crustaceans, worms, and other species, show that co-exposure to NPls significantly increases the toxicity of various metals, including Cd, As, Hg, Pb, Ag, Ti, and Cu, to name a few. Furthermore, the synergistic effect of joint exposure to metals and NPls are more pronounced compared to co-exposures to metals with MPls. Furthermore, NPls act as vectors for metals, increasing their bioavailability and promoting metal-induced oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, pyroptosis, and ferroptosis, when compared to single metal exposures. Several studies have also shown that NPls contribute to the activation of cuproptosis. In addition, NPls aggravate metal-induced gut dysbiosis and alterations in microbiota metabolomics, resulting in altered functioning of gut-brain and gut-liver axes. Epigenetic mechanisms, including modulation of non-coding RNA expression, may also underlie the synergistic toxic effects of co-exposure to NPls and metals. Despite growing evidence for the biological significance of NPls–metal interactions, substantial gaps remain regarding environmentally realistic exposure levels, the physicochemical determinants of synergy, and the relevance of current models to human health. Future research should integrate advanced mechanistic tools, standardized exposure frameworks, and real-world scenarios to clarify the risks associated with combined NPls and metal exposures.