The POLYRISK project aims unraveling the risks of microplastic and nanoplastic particles (MNP) that are ubiquitous in our environment and are likely to be entering the human body via inhalation and ingestion. The most bioavailable low-micron and nano-sized MNP, pose the biggest analytical challenges or today’s analytical chemists. Existing knowledge about the adverse pro-inflammatory effects of airborne particulate matter and nanoparticles, combined with pro-inflammatory evidence of MNP exposure observed in animal models and in vitro pilot tests with human immune cells, suggests that MNP may cause immunotoxicity in humans. Occupational exposure of workers to fibrous MNP can indeed lead to granulomatous lesions, causing respiratory irritation, functional abnormalities and flock worker’s lung. Currently, human health risk assessment protocols specific to MNP are not available and key data is missing. This hampers science-based decision making. On this backdrop, POLYRISK’s human risk assessment strategy will combine highly advanced sampling, sample pretreatment and analytical methods to detect MNP in complex matrices, up-to-date fit-for-purpose hazard assessment technologies and multiple real-life human exposure scenarios. We will focus on key toxic events linked to several chronic inflammatory diseases. The consortium uniquely brings together interdisciplinary experience and know-how on quality-controlled chemical analyses of MNP and additives, intestinal and respiratory toxicity models, human exposure epidemiology, immunotoxicology and real-life high-exposure studies. POLYRISK’s novel human risk assessment strategy is based on mechanistic reasoning and pragmatically accommodates the complexity of the MNP toxicant class. Building with ground-breaking science, stakeholder engagement and strong communication, POLYRISK aims to rapidly reduce current MNP risk uncertainties and support EU efforts to ensure public health is adequately protected from the potential risks of MNP pollution. POLYRISK is a part of the European cluster on Health Impacts of Micro- and Nanoplastics.