A system-of-systems (SoS) is inherently open inconfiguration and evolutionary in lifecycle. For the nextgeneration of cooperative cyber-physical system-of-systems,safety and security constitute two key issues of public concernthat affect the deployment and acceptance. In engineering, theopenness and evolutionary nature also entail radical paradigmshifts. This paper presents one novel approach to thedevelopment of qualified cyber-physical system-of-systems, withCooperative Intelligent Transport Systems (C-ITS) as one target.The approach, referred to as knowledge-in-the-loop, aims toallow a synergy of well-managed lifecycles, formal qualityassurance, and smart system features. One research goal is toenable an evolutionary development with continuous andtraceable flows of system rationale from design-time to postdeploymenttime and back, supporting automated knowledgeinference and enrichment. Another research goal is to develop aformal approach to risk-aware dynamic treatment of safety andsecurity as a whole in the context of system-of-systems. Key basetechnologies include: (1) EAST-ADL for the consolidation ofsystem-wide concerns and for the creation of an ontology foradvanced run-time decisions, (2) Learning Based-Testing for runtimeand post-deployment model inference, safety monitoringand testing, (3) Provable Isolation for run-time attack detectionand enforcement of security in real-time operating systems.