Host-Derived Intestinal Extracellular Vesicles Inhibit Polystyrene Microplastic-Induced Activation of Inflammation and Autophagy in Macrophages

Polystyrene microplastics (PS-MPs), as pervasive environmental contaminants, infiltrate the human body primarily via the food chain and accumulate in intestinal tissues, where they provoke inflammatory responses and disrupt cellular homeostasis. Although intestinal epithelial cell-derived extracellular vehicles (I-EVs) are recognized for their regulatory roles in maintaining gut integrity, their potential protective effects against PS-MP-induced intestinal inflammation and autophagy remain poorly understood. In this study, we investigated the impact of host-derived I-EVs on PS-MP-triggered inflammatory and autophagic responses in macrophages. Exposure of RAW264.7 cells and primary mouse peritoneal macrophages to PS-MPs (50 nm, 50-200 μg/mL) activated the TLR4/NF-κB signaling pathway and upregulated the autophagy marker LC3B. Notably, treatment with I-EVs (50 and 100 μg/mL) dose-dependently attenuated PS-MP-induced inflammation by suppressing the MyD88/NF-κB axis and downregulating TNF-α and IL-6 expression. Furthermore, I-EVs significantly reduced LC3B levels and inhibited autophagic activation. Mechanistically, I-EVs competitively hindered PS-MP binding to macrophages, thereby preventing its cellular internalization. Collectively, our findings reveal that host-derived I-EVs mitigate PS-MP-induced macrophage inflammation and autophagy by blocking cellular uptake of PS-MPs and modulating key intracellular signaling pathways. This study not only deepens the understanding of microplastic toxicity but also highlights the potential of exploiting endogenous vesicular systems as a strategic intervention against environmental plastic pollution.