We have analyzed the effects on Drosophila melanogaster intestines and two human cell lines of intestinal origin of two different nano-enabled food additives belonging to the persistent or slowly soluble engineered nanomaterials (NM): silicon dioxide E551 and titanium dioxide E171. These compounds are considered as high priority for toxicological testing. Our analysis combines the advantages of a model organism (Drosophila) with the mechanistic approaches feasible in cellular models. We evaluated general cytotoxicity in both models, and selected 10 and 100 μg mL⁻¹ as exposure concentrations that do not compromise cellular or organism viability. We identified changes in the expression levels of a selected set of genes related to the regulation of oxidative stress and DNA integrity. Interestingly, these changes were in the same direction when comparing Drosophila intestines and human differentiated Caco-2 cells, indicating a conservation in the general cellular response to E551 and E171 exposure in both systems. The use of Drosophila offers unique opportunities in the anatomical, physiological and biochemical analysis of the exposure to engineered nanomaterials, as it complements in vitro approaches in an experimental setting that reproduces many of the biological characteristics of the human intestine. Drosophila is relatively inexpensive, genetically versatile and compliant with 3R principles, and consequently we expect that its use will contribute to other risk assessment strategies aiming to identify the action mechanisms of toxicants.