<p>Among the various institutional layers that shape the structure and function of regional innovation systems (RIS), the network of research universities (RU) stands out as a principal component, constituting the hubs and channels that facilitate knowledge creation, technology transfer, and skilled workforce development. Here, we analyze the contributions to regional competitiveness associated with (a) local versus cross-border collaboration and (b) prestige signaling associated with a region’s flagship institutions of higher education. By applying hierarchical regression models with institutional fixed effects to research profiles constructed from ~800,000 publications affiliated with 28 RU in California (CA) and Texas (TX), in particular including all University of California and University of Texas campuses, we find that research co-produced with a premier regional university that also extends across international borders features a 21% (CA) and 25% (TX) citation premium. We also show that the citation premiums attributable to institutional prestige and international collaboration have both increased over time relative to other factors. These findings underscore the importance of balancing investment in regional integration with cross-border engagement, as prestige spillovers can enhance regional competitiveness by attracting elite scientists, fostering impactful collaborations, and integrating distant regions within global research networks. Managing RIS thus calls for strategic investments in regional collaboration networks and flagship institutions to balance local benefits while leveraging the capacity to attract external research expertise and capabilities. Within this context, our study helps explain the growing shift towards multi-institutional consortia and RU satellite campuses as mechanisms for harnessing institutional and cross-regional complementarities at scale.</p>