In the last two decades, global cities are addressing climate challenges, by transforming their infrastructural spaces through Climate-adaptive Nature-based regeneration, also aiming to cope with local ecological, social and economic asymmetries. Inside a prevailing technical and performance-based approaches, to date design research around Climate-adaptive Nature-based regeneration of urban infrastructure is limited, failing to impact on current transformations and to be implemented beyond larger cities. Taking advantage from a ‘research by design’ methodology, the research aims to leverage design potential for climate-adaptive green regeneration of infrastructural spaces and mainstream this approach in current practices. With this purpose, an operational Framework is defined, giving both conceptual and operational insight for Climate-adaptive Nature-based Streetscapes that will be tested inside a Southern Europe urban context in the future.