In this study, we investigated the impact of iron-rich nanoparticles derived from different locations in the subway on the innate immune system in blood. Nanoparticles were generated from Third Rail, Rail, and Wheel materials and characterized using several techniques. The response in a human whole-blood model was analyzed using ELISA and capillary immunoelectrophoresis. All nanoparticles were iron oxides, but Third Rail nanoparticles also contained Silicon and were highly thrombo-inflammatory, activating Factor XI-induced coagulation and pro-inflammatory kallikrein/kinin pathways. Wheel and Rail nanoparticles were less reactive, mainly activating the kallikrein/kinin pathway, leading to milder inflammatory reactions. The strong thrombo-inflammatory properties of Third Rail nanoparticles are attributed to their high Silicon content. None of the nanoparticles significantly activated the complement system. In conclusion, we found that the elemental composition of nanoparticles is crucial in determining whether activation leads to kallikrein/kinin system activation and bradykinin release or Factor XI activation and thrombosis.