The research aims to explore the scientific and practical aspects of developing smart transport systems within the digital economy infrastructure in Russia’s regions to ensure national economic security. Drawing on 2023 statistics from the Southern (SFD) and Volga (VFD) Federal Districts of the Russian Federation, the research presents a new meso-level perspective on the country’s economic security, demonstrated through the example of these districts for 2023–2030. This perspective includes, first, an infrastructure-based mechanism for ensuring economic security in Russia’s regions centered on TLC 5.0. Second, it outlines the potential for strengthening regional economic security in the SFD and VFD through 2030 by maximizing the use of the most critical technologies in TLC 5.0. Third, it provides a set of practical recommendations for the development of smart transport systems in the digital economy infrastructure of the SFD and VFD through 2030. The theoretical significance of the results lies in explaining the cause-and-effect relationships that drive changes in national economic security, as reflected at the regional level through the innovative concept of TLC 5.0 infrastructure as a phenomenon of Russia’s digital regional economy. The practical value is embodied in the author’s proposals for the breakthrough development of regional economies and smart transport systems within Russia’s digital infrastructure.