Streptomyces: boost chassis strains for production of invaluable natural products

Streptomyces species continue to occupy a pivotal role in natural product biosynthesis, owing to their unparalleled metabolic diversity and genetic adaptability. This review focuses on cutting-edge advances documented from 2020 to 2025 (encompassing approximately 150 cases), with particular emphasis on innovations in canonical/non-canonical Streptomyces chassis engineering. We synthesize key developments across genome streamlining, mitigation of endogenous interference, redistribution of precursors and cofactors, regulatory circuit reprogramming, optimization of phylogenetic host-cluster compatibility, and enhancement of fermentation robustness. These strategies collectively transform Streptomyces into versatile, application-specific production platforms. A standout innovation highlighted herein is the 5M strategy (Mechanism-Model-Manipulate-Measure-Manufacture), which reframes chassis engineering as an iterative, systems-level process inspired by engineering principles. This framework fosters precise manipulation and strain-bioreactor synergy, based on a deep comprehension of metabolic mechanisms and bioreactor compatibility dynamics, thereby facilitating scalable manufacturing of high-value compounds. By providing a structured roadmap, this perspective equips researchers with actionable insights for advancing next-generation Streptomyces chassis in synthetic biology and industrial biotechnology. Furthermore, we explore emerging technological breakthroughs, such as AI-driven design tools, multiplexed genome editing technologies, and hybrid chemical-enzymatic integration strategies, that are poised to accelerate the evolution toward intelligent, modular chassis architectures. Ultimately, this review offers a practical resource for advancing Streptomyces applications in natural product discovery, functional characterization, and yield enhancement, supporting incremental improvements in biotechnological applications.