While most SwafS initiatives have contributed to strengthening knowledge and approaches to Open Science, few initiatives have explored and implemented an RRI approach to Open Innovation. MOSAIC will address this SwafS knowledge base gap, exploring how to translate the involvement of stakeholders “from all parts of the quadruple helix”, typical of SwafS and RRI, in Open Innovation ecosystems, within the context of a mission-like environment focused on climate neutral and smart cities priorities. Drawing upon the richness of SwafS experiences so far, MOSAIC’s research will lead to the assessment of effective instruments applicable to successful co-creation approaches in quadruple-helix Open Innovation pathways. While doing so, the MOSAIC consortium will define and assess indicators to measure impacts and transformative changes that are specific to this particular context, generating scientific publications as well as toolkits to be further used within future SwafS-like initiatives and beyond. Pilot actions in the cities of Brussels and Milan will test MOSAIC’s methodological approach and research actions throughout the project. The piloting process will produce concrete instruments and recommendations, to be replicated in further European cities and regions willing to engage in mission-oriented approaches via quadruple helix collaboration, but also to enrich the work of Horizon Europe researchers and stakeholders more broadly.