The overwhelming scientific evidence provided by the academic corpus indicates that to tackle the origin and negative impacts of nutrient pollution on water, soil and biodiversity, a wide landscape-river-sea system approach needs to be used. This should work on sustainable land management practices (especially, agricultural ones), improved wastewater treatment, and feasible nature restoration strategies. The project SEACURE will aim at demonstrating, scaling up and replicating effective innovations for the systemic prevention and reduction of nutrient pollution in the Mediterranean Sea basin, in line with the innovation ecosystem framework provided by the ongoing Mediterranean Lighthouse projects (as BlueMissionMed) and in close cooperation with related activities implemented by regional soil health living labs in the area. The project is dedicating resources for the regional upscale and replication of successful nutrient management strategies devoted to: i) reduce soil pollution and enhance its restoration; ii) reduce fertilizers use and nutrient losses; and iii) prevent, minimize and remediate nutrients pollution in freshwater and marine ecosystems, in six territorial units (Mar Menor and Central Catalunya in Spain, Po delta and Esino river in Italy, and Axios river delta and Thessaly Plain in Greece). On one hand, the viability and impact will be evaluated. On the other hand, partners will act on innovation levers: policy uptake, societal awareness, capacity building and funding availability. Regional business plans for upscaling the effective strategies in the territorial units will be crafted, taking advantage of the regional mobilisation of innovation ecosystems already carried out during the project. Finally, the replication of knowledge will be encouraged thanks to the technical assistance to Associated Regions through FSTP grants. In summary, the project is embracing the Missions’ impact-driven approach, working with actors to maximise its results’ uptake.