In recent years, numerous studies have shown that the Regional Innovation System (RIS) approach can make important contributions to the generation of innovation and economic development. Additionally, the key role of Higher Education Institutions (HEIs) in innovation systems has been increasingly acknowledged. Amidst the regulatory changes and ongoing economic progress of the region, the future of the Hong Kong-Shenzhen border region is bound for transformation, but there is a lack of research on its potential development. This study explores RIS theories and analyses the current development status and existing challenges around Hong Kong-Shenzhen cross-border collaboration. It analyses examples of innovation-oriented urban planning strategies and summarizes the key planning, urban design, and management principles that nurture innovation ecosystems comprising of multiple types of stakeholders. Applying these principles to the Lok Ma Chau section of the Hong Kong-Shenzhen border region, the study explores a mixed-use urban planning model that shapes innovative forms of live-work environments, which can attract talent and investment. It concludes that regional economic development can be supported through strategic infrastructure that supports businesses, as well as localised improvements in the quality of living.