Biological Responses to Combined Nanoparticles: Uptake, Distribution and Toxicity.

The biological effects of nanoparticles (NPs) form the basis of their safety assessments and biomedical applications. However, most related studies have focused on exposing biological systems such as cells and animals to individual NPs. This is far removed from real-world environmental exposure and biomedical application scenarios involving NPs. In practice, NPs often coexist with other types of NPs or the same type of NPs of different sizes. Interactions between mixed NPs can alter their dispersion states and biological behaviors, thereby influencing their cellular internalization, distribution, and ultimately determining their toxicity outcomes. In this review, we summarize the research progress and current understanding of the biological effects of mixed NPs. We focus on how co-exposure influences the uptake/absorption, fate, and toxicity of NPs in cells and animals. Co-exposure results in an increased, decreased, or unaffected cellular uptake of NPs by altering their dispersion states and protein corona in biological media, and thus their uptake routes. Cytotoxicity of mixed NPs exhibits patterns of synergistic, antagonistic, or additive effects, and is not always positively correlated with the intracellular contents of the NPs, highlighting the complexity of the response of biological systems to NP co-exposure. In vivo evidence further indicates that co-exposure to NPs can result in alterations in the absorption efficiency, tissue distribution, and clearance of the NPs, and thus their overall toxicity. Finally, we discuss the limitations of the current research on the biological response to mixed NPs, and propose key challenges and future directions towards a more standardized, mechanism-based assessment of NP mixtures.