Toward engineered microbial chassis for growth–production balancing

Abstract

The inherent conflict between cellular growth and product synthesis, arising from limited resource allocation and metabolic burden, fundamentally constrains the performance of microbial chassis. Traditional strategies that focus solely on flux intensification or knockout of competing pathways often face diminishing returns and may compromise cellular fitness, motivating the exploration of alternative engineering paradigms. Emerging approaches aim to modulate the growth–production trade-off across temporal, network-level, and spatial dimensions, thereby reframing this trade-off from a fixed physiological barrier into a tunable design parameter. This review systematically summarizes four complementary strategies: temporal decoupling via dynamic genetic circuits and phase-segregated cultivation; network-level metabolic resource optimization through redistribution of carbon flux, cofactors, and energy; spatial reorganization using enzyme colocalization, organelle compartmentalization, and modular microbial consortia; and digital and intelligent control frameworks that integrate real-time sensing, artificial intelligence (AI)-based prediction, and digital twin–enabled closed-loop optimization. The key insight is that decoupling does not eliminate competition but rather reschedules, redistributes, or relocalizes it, thereby achieving high production without sacrificing cellular robustness. Collectively, these multi-dimensional strategies transform the growth–production trade-off into a programmable engineering variable. Future efforts should focus on simplifying dynamic circuits, improving long-term genetic stability under industrial conditions, developing tools for non-model hosts, and engineering generally recognized as safe (GRAS) organisms with predictable trade-off management, paving the way for next-generation microbial cell factories that are both productive and resilient.