Polystyrene Nanoplastics Perturb Cell Membranes and Induce Bystander Uptake of Diverse Cargos

Polystyrene nanoplastics are ubiquitous environmental pollutants, yet their fundamental physical interactions with cell membranes-and how these interactions alter subsequent cellular uptake mechanisms-remain poorly understood. Here, we interrogate nanoplastic-membrane dynamics using chemically defined model membranes (supported lipid bilayers and giant unilamellar vesicles) and intestinal epithelial cells. We demonstrate that 25 nm polystyrene nanoparticles (PS25) fundamentally perturb lipid bilayers, severely restricting macroscopic membrane fluidity and permanently truncating the mobile lipid fraction (from 96.9% ± 1.7-67.2% ± 1.5%). Correspondingly, PS25 elicits significantly higher cellular internalization, mitochondrial impairment, and cytotoxicity relative to 50 nm particles (PS50). Crucially, we reveal that this massive biophysical membrane remodeling acts as a potent structural trigger for "bystander uptake". Specifically, PS25 facilitates the robust co-internalization of diverse, normally impermeable cargoes (including proteins, peptides, and metal nanoparticles) by 2- to 6-fold across susceptible cell lines. Mechanistic investigations confirm this phenomenon is not driven by chemical carrier-cargo complexation, but by physical membrane deformation that hijacks cholesterol-dependent macropinocytosis and lipid raft-mediated endocytosis. These findings highlight a synergistic mechanism by which nanoplastics can act as physical "entry facilitators", potentiating the intracellular delivery and toxicity of co-existing environmental pollutants, thereby providing essential new insights for comprehensive risk assessment.