According to recent studies, unmanned aerial vehicles (UAV) can play a game-changing part in terms of cost reduction and speed increase to address the last-mile delivery (LMD) problem and also to attend emergencies. Last-mile delivery services are getting more and more relevant, especially when in times where social distance is required. Given this scenario, our paper introduces a cyber-physical (CPS) system roadmap propose applicable for last-mile delivery drones. The proposed CPS guidelines are based on the concept of system of systems to enable an emerging behavior towards smart cities’ governance. In this paper, we also discuss topics from air space control and reservation throughout communication infrastructure and decentralized control supported on a blockchain.