Size- and Dose-Dependent Body-Wide Organ Transcriptomic Responses to Calcium Phosphate Nanomaterials

Nanomaterials are widely used in clinical practice. There are potential risks of body-wide infiltration due to their small size; however, the body-wide reliable risk assessment of nanoparticle infiltration is not fully studied and established. In this study, we demonstrated the size- and dose-dependent body-wide organ transcriptomic responses to calcium phosphate nanomaterials in vivo. In a mice model, a calcium phosphate nanocluster (amorphous calcium phosphate, ACP, similar to 1 nm in diameter) and its crystallization product (ACP-M, similar to 10 nm in diameter) in a series of doses was administrated systematically; multiorgan transcriptomics were then performed with tissues of heart, liver, spleen, lung, kidney, and brain to investigate the systematic effect of dose and size of nanomaterials on the whole body. The results presented gene expression trajectories correlated with the dose of the nanomaterials and tissue-specific risk effects in all detected tissues. For the dose-dependent tissue-specific risk effects, lung tissue exhibited the most significant risk signatures related to apoptosis, cell proliferation, and cell stress. The spleen showed the second most significant risk signatures associated with immune response and DNA damage. For the size-dependent tissue-specific risk effects, ACP nanomaterials could increase most of the tissue-specific risk effects of nanomaterials in multiple organs than larger calcium phosphate nanoparticles. Finally, we used the size- and dose-dependent body-wide organ transcriptomic responses/risks to nanomaterials as the standards and built up a risk prediction model to evaluate the risk of the local nanomaterials delivery. Thus, our findings could provide a size- and dose- dependent risk assessment scale of nanoparticles in the transcriptomic level. It could be useful for risk assessment of nanomaterials in the future.

Automated summary

In this study, the size- and dose-dependent body-wide organ transcriptomic responses to calcium phosphate nanomaterials were investigated. The results showed that the gene expression trajectories correlated with the dose of the nanomaterials and tissue-specific risk effects. Lung tissue exhibited the most significant risk signatures related to apoptosis, cell proliferation, and cell stress, while the spleen showed risk signatures associated with immune response and DNA damage. The study also found that smaller calcium phosphate nanomaterials had greater tissue-specific risk effects in multiple organs compared to larger nanoparticles. A risk prediction model was built based on the findings to evaluate the risk of local nanomaterials delivery. This study provides valuable insights into the size- and dose-dependent risk assessment of nanoparticles at the transcriptomic level.