Hitchhikers in bivalve immune system: Mixed microplastics and nanoplastics triggers hemocyte autophagy

Natural microplastic and nanoplastics (MNPs) mixtures generally consist of multiple sizes, but how their co-existence influences the immune system of aquatic organisms remains elusive. Here, we quantitatively tracked and demonstrated that such heterogeneity dynamically reshaped bivalve hemocyte burden in non-additive modes with subpopulation-specific consequences for immune function. Kinetic modeling revealed distinct internalization patterns and selectivity among hemocyte subpopulations, driven by particle proportions and uptake dynamics. Granulocytes displayed indiscriminate capacity for MNP internalization, maintaining high uptake efficiency across varying particle compositions. In contrast, semigranulocytes showed selective internalization behavior sensitive to particle size distributions, facilitating preferential uptake shifts as nanoparticle proportions varied. Mechanistically, large NPs accelerated the internalization of smaller NPs via a hitchhiking effect but simultaneously competed for intracellular processing pathways, limiting maximal uptake. Notably, co-exposure with smaller NPs significantly enhanced and accelerated MPs internalization, leading to intracellular overload with severe lysosomal damage and mitochondrial impairment. These disruptions potentially triggered mitochondria-lysosome crosstalk and autophagy, particularly pronounced in semigranulocytes. Ultimately, the combined presence of multiple particle sizes resulted in cascading impairment of hemocyte phagocytic capacity than exposure to individual particles alone, highlighting particle-size interactions as critical determinants of immunotoxicity. Our findings underscored how coordinated disposal of hemocyte subpopulations influenced the mixed-size plastic clearance, providing new insight on the health risks posed by MNPs to marine organisms.