When　nanomaterials　are　exposed　to　complex　systems,　such　as　food,　they　may　cause　significant　changes　in　physical　and　chemical　properties　and　even　toxicity.　The　toxicity　evaluation　of　complex　systems　is　urgent.　Unfortunately,　so　far,　there　is　no　database　established　about　the　toxicity　changes　of　nanoparticles　in　composite　systems.　In　this　paper,　the　changes　and　toxicity　mechanism　of　zinc　oxide　nanoparticles　(ZnO　NPs)　in　a　composite　system　are　studied.　The　results　show　that　the　dissolution　of　zinc　ions　(Zn2+)　in　acidic　systems　(vitamin　C,　tartaric　acid,　or　citric　acid)　increases　the　toxicity　of　ZnO　NPs.　However,　the　toxicity　of　ZnO　NPs　is　reduced　by　the　complexation　effect　with　Zn2+　in　phosphoric　acid,　phosphate,　and　glutathione　systems.　The　influence　of　titanium　dioxide　nanoparticles　(TiO2　NPs)　on　the　toxicity　of　ZnO　NPs　depends　on　size　and　surface　properties.　In　brief,　the　intracellular　Zn2+　homeostasis　level　is　the　decisive　factor　in　determining　the　toxicity　change　in　complex　systems.　The　results　indicate　that　the　toxicity　changes　are　very　different　in　combined　systems,　which　may　have　potential　food　safety　issues,　especially　for　unstable　nanoparticles.