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The study on micro/nanoplastic pollution should embrace complexity. Here, we aim to develop an aquatic environmental system-based comprehensive assessment approach of micro/nanoplastic impacts (ACAM) to evaluate the effects of micro/nanoplastics on aquatic ecosystems from the global environmental change (GEC) and systematic perspective. A case study for freshwater systems in Saskatchewan, Canada was conducted to evaluate the comprehensive effects of multiple GEC factors (polystyrene-nanoplastics (PS-NPs), N, P, salinity, dissolved organic matter (DOM), pH, hardness) on Asterococcus superbus based on ten ecologically relevant endpoints. It is found that at the cellular level, PS-NPs and N had an antagonistic interaction on microalgal growth in the Saskatchewan freshwater ecosystem; at the molecular level, the PS-NP-induced changes in lipid composition in microalgae were regulated by P, DOM, and pH. The significance ranking of factor effects suggested that instead of PS-NPs pollution, the fluctuations in pH level, DOM and N concentrations should be paid attention to first in Saskatchewan. Under the combined impact of PS-NPs and other GEC factors, microalgae at station 14 (Qu'Appelle River near highway 56) might have the minimum growth rate with [−0.048, 0.094] d-1 in Saskatchewan. These findings demonstrate the efficacy of the developed ACAM in a more comprehensive and context-specific assessment of MNP risks, providing new insight for the management of MNP pollution. [Display omitted] • A systematic assessment method for MNP impacts is developed embracing complexity. • Interactions among MNPs and other global environmental change factors are revealed. • The significance of MNP pollution and other environmental problems is prioritized. • Composite effects from multiple global environmental change factors are assessed. [ABSTRACT FROM AUTHOR]