Gut and Glomerular Barriers Determine Nanoplastic Fate and Systemic Impact

Abstract Nanoplastics (NPs) are increasingly recognized as pervasive environmental toxicants, however, their interactions with gut and renal barriers, and the resulting systemic consequences remain poorly understood. Here, we studied the uptake of 50 nm polystyrene (PS) nanoparticles using a multi-scale approach integrating zebrafish models, isolated perfused mouse kidneys, and in vitro assays to delineate uptake and barrier-dependent organ distribution. In zebrafish larvae, PS-NPs were efficiently absorbed via the intestinal tract, as visualized by confocal and label-free stimulated Raman scattering (SRS) microscopy, leading to gut microbiota dysbiosis and systemic inflammatory responses. Despite widespread systemic dissemination, renal accumulation was minimal under physiological conditions, whereas both zebrafish and isolated perfused mouse kidneys exhibited substantial PS-NPs retention only when the glomerular filtration barrier was disrupted. In vitro glomerular endothelial cells and podocytes readily internalized PS-NPs without altering key glomerular identity markers, highlighting their intrinsic uptake capacity that is normally restricted in vivo by barrier integrity. Our findings establish the glomerular filtration barrier as a crucial gatekeeper that prevents renal nanoplastic deposition. Furthermore, we revealed a microbiota-mediated axis that may prime the kidney for the environmentally induced stressing in long term.