Micro- and nanoplastic (MNP) pollution has emerged as a pervasive environmental and food safety issue that has exceeded the planetary safe operating space, with documented toxicological effects spanning all levels of biological organization and raising significant concerns for human health. Nonetheless, the inherent heterogeneity of MNPs, combined with the high diversity of species, model systems and exposure scenario’s used in MNP toxicology research, complicates extrapolation of results and hampers cross-study comparisons. Consequently, the fragmented evidence at present is insufficient to support a comprehensive risk assessment of MNPs. To advance the current state-of-the-science beyond problem identification and towards solution-oriented comprehensive risk assessment, I will develop an evidence-based Adverse Outcome Pathway (AOP) network, building on reported molecular and cellular events triggered by micro- and nanoplastic exposure (WP1). Subsequently, to increase understanding of the reported variability in MNP toxicology the developed AOP network will be refined by integrating biological complexity, both between species and between tissues (WP2), and inherent MNP heterogeneity (WP3). The approach not only advances a comprehensive MNP effect assessment for environmental and human health but also supports development of testing strategies and transitioning to safer-by-design plastic materials, paving the way toward a sustainable future.