Although infant nanomaterial exposure is a worldwide concern, breastfeeding transfer of transition metal-oxide nanoparticles to as well as their toxicity to offspring are still unclear. Breastfeeding transmits nutrition and immunity from mothers to their offspring; it also provides a portal for maternal toxins to enter offspring. Thus, a toxicology assessment of both mothers and their offspring should be established to monitor nanomaterial exposure during lactation. Here, we determined the effects of the exposure route on the biodistribution, biopersistence, and toxicology of nanoparticles (titanium dioxide, zinc oxide, and zirconium dioxide) in both mouse dams and their offspring. Oral and airway exposure routes were tested using gavage and intranasal administration, respectively. Biodistribution in the main organs (breast, liver, spleen, lung, kidney, intestine, and brain) and biopersistence in the blood and milk were determined using inductively coupled plasma mass spectrometry. Hematology and histomorphology analyses were performed to determine the toxicology of the nanoparticles. A reduced offspring body weight was found with the reduced nanoparticle size. Furthermore, both oral and airway exposure increased the nanoparticle concentrations in the main tissues and milk. More nanoparticles were transferred into maternal tissues and milk via airway exposure than via oral exposure. During the transfer of the metal from the exposed nanoparticles to milk, the immune cell pathway played a more important role in the airway route than in the oral exposure route. Finally, maternal exposure via both the oral and airway routes reduced the body weight and survival rate of their breastfeeding offspring, which could possibly be attributed to the toxicity of nanoparticles to blood cells and organs. In conclusion, maternal exposure to nanoparticles led to a reduced body weight and survival rate in breastfed offspring, and nanoparticle exposure via the airway route led to a higher immune response and tissue injury than that via the oral exposure route. This study suggests that the use of products containing metal nanoparticles in breastfeeding mothers and their offspring should be reconsidered to maintain a safe breastfeeding system. Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.