The chemical and catalytic activity of nanoparticles has strongly contributed to the current tremendous interest in engineered nanomaterials and often serves as a guiding principle for the design of functional materials. Since it has most recently become evident that such active materials can enter into cells or organisms, the present study investigates the level of intracellular oxidations after exposure to iron-, cobalt-, manganese-, and titania-containing silica nanoparticles and the corresponding pure oxides in vitro. The resulting oxidative stress was quantitatively measured as the release of reactive oxygen species (ROS). The use of thoroughly characterized nanoparticles of the same morphology, comparable size, shape, and degree of agglomeration allowed separation of physical (rate of particle uptake, agglomeration, sedimentation) and chemical effects (oxidations). Three sets of control experiments elucidated the role of nanoparticles as carriers for heavy metal uptake and excluded a potential interference of the biological assay with the nanomaterial. The present results indicate that the particles could efficiently enter the cells by a Trojan-horse type mechanism which provoked an up to eight times higher oxidative stress in the case of cobalt or manganese if compared to reference cultures exposed to aqueous solutions of the same metals. A systematic investigation on iron-containing nanoparticles as used in industrial fine chemical synthesis demonstrated that the presence of catalytic activity could strongly alter the damaging action of a nanomaterial. This indicates that a proactive development of nanomaterials and their risk assessment should consider chemical and catalytic properties of nanomaterials beyond a mere focus on physical properties such as size, shape, and degree of agglomeration.