Upstream design enabling downstream simplification in biomanufacturing: strategies and perspectives

In industrial biomanufacturing, downstream processing (DSP) remains a primary determinant of economic viability and operational complexity. While conventional process optimization focuses on refining reaction units, a transformative paradigm of "upstream design enabling downstream simplification" has emerged. This review systematically evaluates five representative microbial engineering strategies to streamline DSP: secretion pathway engineering, product modification, cell surface engineering, cell morphology engineering, and programmed cell lysis. These upstream interventions decouple product synthesis from complex separation matrices and lower separation costs by promoting extracellular secretion, facilitating intracellular product release, or enabling targeted purification. By systematically summarizing the principles, applications, and advantages, this review provides a strategic framework for developing next-generation microbial cell factories that harmonize upstream productivity with downstream efficiency, ultimately paving the way for more cost-competitive and sustainable bio-production.