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GMOs have become an important part of a sustainable bio economy, with a wide range of uses in agriculture, bioenergy, and healthcare. The fast growth of GMOs and allied synthetic biology technologies, on the other hand, presents a variety of biosecurity issues about GMO environmental escape, detection, and effect on native ecosystems. From traditional auxotrophies to global genome recoding, a variety of genetic protections have been implemented in a variety of microbial hosts. However, a greater knowledge of the basic principles driving microbial responsiveness to biocontainment limitations and GMO interaction with the environment is necessary to achieve the full potential of microorganisms as bio catalytic platforms in the bio economy. We examine current analytical biotechnological advancements and methodologies for assessing biocontainment and microbial bio productivity, as well as prospects for predictive systems bio designs to ensure a successful bio economy, in this paper.