Abstract Body: Introduction
Nanoplastics (NPs; < 1 µm) formed by environmental photooxidation of larger plastics have recently been detected in human brain and cardiovascular tissues. This observation indicates that NPs undergo systemic distribution within the body. As micro and nanoplastics in natural environments are routinely exposed to ultraviolet irradiation that induces photooxidative aging, the underlying mechanisms by which photoaged plastic particles traverse biological barriers and influence organ function remain poorly elucidated. Therefore, we hypothesized that photoaged nanoplastics impair endothelial Piezo1-mediated mechanotransduction, thereby a compromise of gut-vascular barrier integrity and subsequently systemic translocation.

Methods and Results
Pristine nanoparticles (NPs) were subjected to ultraviolet irradiation for 4 weeks to generate photoaged microplastics (PA-MPs; >1.2 µm), which displayed irregular morphologies by SEM and formed intracellular aggregates detectable by a particle-associated fluorescent probe. AFM showed that PA-MPs increased endothelial stiffness, while transcriptomic profiling revealed enrichment of inflammation-related pathways and suppression of programs associated with junction assembly, cytoskeletal organization, cell migration, and transcriptional regulation. These changes aligned with reduced junctional protein expression and impaired transwell migration, indicating compromised cell–cell junction. Functional analyses demonstrated impaired calcium entry through mechanosensitive ion channels (Piezo1, TRPV4, and TRPC6) and suppression of Notch signaling, without changes in Piezo1 protein or mRNA levels. In vivo, microgavage of PA-MPs in Tg(flk1:EGFP) zebrafish larvae compromised vascular barrier integrity and anticipated particle translocation intot hte systemic circulation. Moreover, PA-MPs suppressed Notch-positive endothelial cells in Tg(Tp1:EGFP) larvae, showing a pattern comparable to endothelial-specific piezo1 inhibition. Consistent with these findings, PA-MPs reduced neuronal calcium activity in the zebrafish brain and myocardial calcium transients, with changes in swimming behavior and reduced endurance.

Conclusion
Our findings suggest that environmentally aged microplastics impair endothelial Piezo1-mediated mechanotransduction, which compromises vascular barrier integrity and supports systemic distribution, together with dysregulation of neural and cardiac calcium transients and associated functional consequences.