Polystyrene nanoplastics modulate VGLL3 phase separation by enhancing intermolecular interactions: implications for fibrosis and beyond

Microplastics and nanoplastics (MNPs) are widespread environmental pollutants associated with diverse health risks, yet their impact on protein liquid-liquid phase separation (LLPS) in fibrosis remains poorly understood. Here, we focus on vestigial-like family member 3 (VGLL3), a transcriptional cofactor implicated in fibrosis, to investigate whether polystyrene nanoparticles (PS NPs) with defined surface chemistries and sizes modulate its phase behavior. The results revealed that PS-COOH NPs robustly and selectively induced VGLL3 LLPS in a concentration- and size-dependent manner, with re-entrant dissolution at higher NP fractions. In contrast, PS NPs and PS-NH₂ NPs exert only minor effects. The condensates were sensitive to 1,6-hexanediol, indicating their dynamic and reversible nature. Dynamic light scattering (DLS) revealed right-shifted size distributions consistent with higher-order NP–protein complexes, whereas a negatively charged oligonucleotide failed to trigger LLPS, suggesting that charge alone is insufficient. Molecular docking supports a scaffold model in which PS-COOH NP surfaces stabilize multivalent hydrogen-bonding and hydrophobic contacts between VGLL3 molecules. Collectively, these findings provide a mechanistic basis for how carboxylate-rich/aged MNPs can remodel condensates of a fibrosis regulator, offering a framework to assess MNP health risks and to guide the design of safer or condensate-targeting nanomaterials.