Pathogenesis of Micro/Nanoplastics in Mammalian Systems: Gut to Systemic Multi-Organ Dysfunction.

Micro- and nanoplastics (MNPs) have emerged as widespread environmental contaminants with growing implications for human health. Growing evidence indicates that the gastrointestinal tract is not only the primary site of exposure but also a central regulator of systemic toxicity through interactions among the intestinal barrier, immune system, and gut microbiota. Consequently, research has shifted from describing tissue accumulation to elucidating how intestinal dysfunction drives multi-organ effects via the gut-organ axis. This review summarizes recent advances in mechanisms by which ingested MNPs disrupt intestinal homeostasis and subsequently affect extraintestinal organs. We first examine how particle size, morphology, surface properties, environmental weathering, and polymer chemistry shape intestinal responses. Particular attention is given to the emerging view that biodegradable plastics, despite lower environmental persistence, may produce bioactive degradation products in the gastrointestinal tract that alter host-microbiota metabolism. We then integrate current evidence on how barrier disruption, microbial dysbiosis, altered microbial metabolites, and immune signaling mediate communication along the gut-liver, gut-brain, gut-lung, and gut-endocrine axes. In addition, we compare commonly used experimental models, highlighting their respective strengths and limitations for mechanistic studies and translational research. Finally, we discuss intervention strategies and key challenges, including environmentally realistic exposure assessment, methodological standardization, long-term biological adaptation, and the development of human-relevant models. Overall, MNP toxicity arises from dynamic interactions between particle properties and host responses rather than burden alone. Ultimately, MNP risk assessment should move beyond the "particle-accumulation" paradigm toward a "systemic-disruption" framework, where the gut is recognized as a biological amplifier of exposure and functional homeostasis takes precedence over particle burden.