Central Europe (CE) has a high potential of transnational cooperation opportunities to promote bottom-up implementation of RIS3 strategies, but many remain unexploited. S3HubsinCE unleashes this potential, by generating a transnational support structure in 10 CE areas, based on connected Digital Innovation Hubs (DIH), creating stronger links between RIS3 stakeholders & promoting strategic cooperation between triple-helix & quadruple-helix institutions in key CE-relevant Technology Priority Areas (TPAs) (i.e. advanced manufacturing & materials, ICT, nanotech, biotech & medical devices). The transnational structure develops by (1) creating & connecting the CERIS3 Navigation Crews (OT1.1) & applying a common Digital Integration Toolkit (OT1.2); (2) linking existing & building DIHs (a stable sustainable structure for CERIS3 cooperation) in CE/EU (OT2.2) with an aligned transnational Strategy & Action Plan for CERIS3 Excellence (OT2.2) of 60 pilot actions; (3) fostering the Foundation for Future Foresight (OT3.1), implementing CE’s first RIS3 Investment Forum (OT3.2) & developing the Policy & Technology Blueprints (OT3.3). The approach focuses on setting a future-robust, long-term oriented, strategic framework to enable policy makers & stakeholders to concretely improve & optimise CE RIS3 to gain more benefit out of regional & national S3. The PPs, ASPs, key target groups (TGs - SMEs, multi-level Authorities, RTD, etc.) benefit from the outputs & approach, as it goes beyond current practices in participating regions & chosen TPAs, creating a novel method to design, manage & introduce innovation in the frame of RIS3, through the DIH structure, while assuring value for money & promoting closer to market actions. A transnational setting is critical to gain more & improved results; long-term relations among regions, policy makers, stakeholders, TGs & well-structured practicable working structures/processes are needed to meet CE/EU goals on strengthening R&I development.