Trojan Horse Effect of Biologically Aged Microplastics-An Intracellular Carrier of LPS for Licensing Noncanonical Inflammasome Activation

Microplastics (MPs), due to their poor degradability, can accumulate in the body following ingestion. Most studies evaluating MP safety use pristine particles or those aged for a short period, thus overlooking the long-term physicochemical changes that MPs undergo once they are trapped in tissues. In this study, we observed pronounced alterations in the surface properties of polystyrene MPs after one year of exposure to artificial body fluids, including increased surface roughness and hydrophilicity. These changes enhanced the adhesion of biomolecules, such as lipopolysaccharide (LPS), a typical pathogen-associated molecular pattern (PAMP). Biomechanical analysis confirmed strong interactions between aged MPs and LPS. Once phagocytosed by macrophages, LPS-loaded aged MPs caused phagolysosomal damage and pyroptosis through noncanonical caspase-11 inflammasome activation, which in turn amplified canonical caspase-1-dependent inflammation. Importantly, the inflammatory impact of aged MPs was further validated in vivo in a dextran sulfate sodium (DSS)-induced colitis model in which aged MPs aggravated disease severity. Collectively, these results identify aged MPs as “Trojan horses” with enhanced ability to transport harmful extracellular biomolecules like LPS into the cytoplasm, thereby reprogramming inflammasome signaling. This study highlights particulate stimuli, such as aged MPs, as a previously unrecognized bridge-linking PAMPs with danger-associated molecular patterns (DAMPs).