Environmental aging alters the toxicity profiles of nanoplastics and generates biologically active soluble products.

Nanoplastics (NPs) health risks are widely recognized, yet assessments largely regard particles as the principal toxic entity and overlook soluble aging products generated during environmental exposure. Here, we examine how environmental aging alters NP toxicity profiles and generates biologically active soluble products. Polystyrene (PS) and polymethyl methacrylate (PMMA) NPs were subjected to long-term (365 days) solar-relevant UV aging (315-400 nm) to provide an environmentally realistic framework for evaluating transformation-driven effects. By physically separating aged particles from low-molecular-weight aging products, we found that aging attenuated particle-associated toxicity while generating products that retained substantial biological activity. Integrated histological, transcriptomic, and metabolomic analyses of blood, gut, liver, and brain revealed distinct patterns of tissue injury and metabolic disruption across aged particle and aging product exposures. Aged particles induced fewer and weaker hepatic transcriptional changes than pristine particles, whereas soluble fractions mainly affected circulating metabolism, with 70 and 30 differential serum metabolites for PMMA and PS, respectively. Multi-omics integration and targeted manipulation of gut bacteria linked both components to microbiome-dependent modulation of host metabolism. Environmental aging therefore altered NP toxicity profiles and generated biologically active soluble fractions, highlighting the importance of evaluating residual particles and soluble aging-associated fractions separately.