Plastic has become so pervasive in the modern environment that it now travels through the food chain and into the deepest recesses of the human body. Fragments smaller than five millimetres, known as microplastic and nanoplastic particles, shed from packaging, textiles and countless consumer products, have been detected in human lungs, blood, placenta, brain and breast milk. Some estimates suggest people may ingest between one and five grams of plastic every week, roughly the weight of a credit card. Yet the biological consequences of this constant, low-level exposure have remained frustratingly unclear, largely because most laboratory studies have relied on doses and conditions that bear little resemblance to real life. A new study published in Nature Metabolism now offers one of the most detailed pictures to date of what happens when plastic particles settle inside a living body, and the answer depends, surprisingly, on the size of the particles themselves.
The research, led by Nikola Makdissi, Maria Francesca Viola and Elvira Mass at the University of Bonn, together with a large interdisciplinary team across Germany, Austria and Sweden, set out to trace where ingested plastic goes and what it does once it arrives. The team used carboxylated polystyrene particles of defined sizes, ranging from 50 to 500 nanometres, quality-controlled by dynamic light scattering, and administered them to young male mice either as a single oral dose or through a chronic twelve-week feeding regimen designed to mimic continuous human exposure. Fluorescent labelling allowed the researchers to follow the particles through the body with flow cytometry and microscopy, while gold-core-labelled particles enabled visualisation at the ultrastructural level by electron microscopy.
The first striking finding concerned geography. Within twenty-four hours of a single oral dose, plastic of every size tested had crossed the intestinal barrier and accumulated in the liver and spleen, where it was taken up almost exclusively by macrophages, the resident scavenger cells of the immune system. Particles of 100 nanometres or smaller also reached the brain, preferentially lodging in microglia, the brain’s own macrophage population, whereas the larger 300 to 500 nanometre particles were undetectable there. During chronic feeding, the particles concentrated in the liver, spleen and brown adipose tissue but not in blood, bone marrow, lymph nodes or the small intestine. Within the liver, the primary reservoir was unambiguous: Kupffer cells, the liver-resident macrophages that line the sinusoidal blood vessels and stand guard against everything the gut sends into circulation.
Quantifying exactly how much plastic accumulates in tissues proved unexpectedly difficult, and the team was candid about the methodological obstacles. Europium-spiked particles lost their signal within hours of oral administration, and pyrolysis gas chromatography–mass spectrometry, a widely used technique for detecting plastics in biological samples, suffered from substantial overlap between tissue-derived lipid signals and the spectral markers of polystyrene. In some cases, samples from exposed animals yielded values comparable to or lower than untreated controls. These results align with recent critiques of pyrolysis-based quantification and underscore a broader problem for the field: without reliable measurement tools, assessing human risk remains an inexact science.
Despite the dosing challenges, the biological consequences of chronic exposure were clear and, crucially, size-dependent. After twelve weeks of weekly gavage with 500 nanometre microplastics, mouse livers showed impaired glycogen storage, increased neutral lipid deposition and elevated levels of specific lipid species, including lysophosphatidylethanolamines, lysophosphatidylcholines and monoglycerides. Nanoplastics of 50 nanometres produced none of these hepatic changes. Single-nucleus RNA sequencing revealed that hepatocytes, the liver’s metabolic workhorses, were by far the most transcriptionally responsive cell type, despite not accumulating detectable plastic themselves. Both particle sizes suppressed de novo lipogenesis while increasing fatty acid uptake, but only microplastics downregulated the very-low-density lipoprotein secretory machinery, impairing the cell’s ability to export lipid and tipping the balance toward net retention.
The mechanism appears to run through the macrophages. When Kupffer cells isolated from microplastic-exposed mice were co-cultured overnight with healthy hepatocytes, the hepatocytes accumulated lipid droplets, demonstrating that signals from plastic-laden macrophages are sufficient to induce fatty changes in otherwise normal liver cells. Transcriptomic and proteomic profiling of the exposed Kupffer cells revealed a coordinated reprogramming centred on increased HIF-1α activity and upregulation of apolipoproteins including APOA1, APOA2 and APOC3, proteins known to regulate lipid delivery to hepatocytes. Notably, this reprogramming occurred without classical inflammation: immune cell infiltration, serum cytokines and fibrosis markers were all unremarkable, suggesting the plastic quietly rewires macrophage function rather than triggering an overt immune alarm.
Perhaps the most concerning finding was functional. Microplastic exposure, but not nanoplastic exposure, impaired the phagocytic capacity of Kupffer cells, their fundamental ability to engulf and clear targets from the bloodstream. After just four weeks of exposure, before any lipid accumulation was visible, mice given microplastics cleared antibody-opsonised platelets less efficiently than controls. The defect extended to host defence: when mice were intravenously challenged with Escherichia coli, the blood of microplastic-exposed animals contained significantly more surviving bacteria, indicating compromised systemic bacterial clearance. Because Kupffer cells are central to clearing infected red blood cells in diseases such as malaria, the authors suggest that chronic plastic exposure could have broader implications for blood-borne infections.
Lineage-tracing experiments added another layer of complexity. After twelve weeks of exposure, nearly all Kupffer cells remained of yolk-sac embryonic origin, showing that plastic accumulation does not kill the cells or trigger replacement by bone-marrow-derived monocytes. But when the researchers deliberately depleted Kupffer cells with diphtheria toxin in microplastic-exposed mice, the monocyte-derived replacements failed to fully repopulate the empty niche even twelve weeks later, despite normal monocyte recruitment and differentiation. Plastic exposure therefore appears to impair the long-term maintenance of macrophages within the liver niche, possibly by altering signals from neighbouring endothelial or stellate cells, compounding the functional deficits of the original cells.
The systemic picture grew more intricate when the researchers combined plastic exposure with a high-fat diet. Under metabolic challenge, nanoplastic-exposed mice developed impaired glucose tolerance and elevated fasting glucose, yet paradoxically showed reduced hepatic lipid content, increased oxygen consumption even during cold exposure, reduced fat mass and preserved lean mass, without any change in food intake or activity. This suggests nanoplastics shift whole-body energy balance toward enhanced peripheral lipid burning and thermogenesis. Microplastic-exposed mice, by contrast, showed exacerbated hepatic lipid accumulation under the high-fat diet. The two particle sizes thus produce distinct metabolic syndromes: microplastics clog the liver’s lipid handling through macrophage dysfunction, while nanoplastics perturb systemic glucose and energy regulation.
There was one note of cautious reassurance. After a six-month washout period following the twelve-week exposure, metabolic alterations in the liver had largely resolved, even though plastic particles remained detectable within Kupffer cells. This indicates that unoccupied macrophages can resume their housekeeping functions once exposure ceases, though the persistence of the particles themselves raises unresolved questions about long-term consequences. The authors also emphasise important limitations: the study was conducted mainly in young male mice, which develop diet-induced steatosis faster than females, and the doses used, while lower than in many prior studies, still exceed estimated human exposure. Whether similar size-dependent effects occur in humans, and whether chronic plastic exposure accelerates progression from simple fatty liver to inflammatory liver disease, remain open questions. What the study establishes firmly is that plastic is not biologically inert once inside the body, that macrophages are its first and most burdened hosts, and that particle size is a critical determinant of the damage it does.
Subject of Research: Size-dependent effects of microplastic and nanoplastic exposure on Kupffer cell function and liver and systemic metabolism in mice
Article Title: Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism
Article References: Makdissi, N., Viola, M. F., Steinheuer, L. M., Blank-Stein, N., Kardinal, R., Musacchio, F., Franco Taveras, E., Aliprandi, V., Sieckmann, K., Abdulkadyrov, A., Mayer, M. L., Diefenbach-Wilke, M.-L., Fink, D., Beckert, H., Böhmdorfer, S., Deveuve, Q., Graelmann, F. J., Mauel, K., Kronau, N., … Mass, E. (2026). Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism. Nature Metabolism. https://doi.org/10.1038/s42255-026-01615-8
Image Credits: AI Generated
DOI: 10.1038/s42255-026-01615-8
Keywords: microplastics, nanoplastics, Kupffer cells, macrophages, liver metabolism, phagocytosis, hepatocytes, lipid metabolism, glucose tolerance, plastic pollution, Nature Metabolism, mouse study
