Background: Systemically administered nanoparticles (NPs) designed for biomedical applications are retained in liver and spleen where they become rapidly phagocyted by tissue macrophages leading to inflammation. Methods: To gain insight into the NP-immune cell interaction in liver spleen and lungs, we followed the distribution of molybdenum nanoparticles (MoNPs) in vivo by X-Ray Fluorescence Imaging (XRF) and examined the NP-macrophage interaction and physiological response in these organs. Results: XRF imaging showed that intravenously administered MoNPs transiently accumulate in lungs, liver, and spleen. This leads to increments in the number of Kupffer cells (KC), natural killer (NK) cells, oxidative stress, and inflammation. Macrophage phenotype switched from pro- to an anti-inflammatory. In parallel genes with immunoregulatory and cytoprotective functions were expressed to maintain homeostasis. Nanoparticle uptake in spleen was operated by CD169/Siglec1 splenic macrophages indicating initiation of a secondary immune response. Silica coating reduced nanoparticle toxicity. Conclusion: The innate immunoresponse to NP uptake in liver and spleen is similar to viral or bacterial infections in these organs. A possible secondary immunoresponse to NPs can be primed in spleen aided by CD169/Siglec1 splenic macrophages. Silica coating of metal NPs tunes down this response.