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Combinatorial biosynthesis is a strategy in metabolic engineering and synthetic biology that involves the systematic reassembly, modification, or recombination of biosynthetic genes, enzymes, or gene clusters to generate novel or variant metabolic pathways and, consequently, structurally modified natural product derivatives ^[1]. The approach exploits the modular architecture of biosynthetic enzyme systems—most notably polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs)—to create chemical diversity by swapping, deleting, or rearranging functional domains, altering substrate specificity, or combining biosynthetic elements from distinct native pathways ^[2]. Many biosynthetic pathways are organized into modular gene clusters encoding assembly-line-like megasynthases, whose domain architecture can be rationally or semi-randomly reconfigured to produce libraries of structurally diversified compounds ^[3]. Combinatorial biosynthesis is distinguished from precursor-directed biosynthesis, which relies on feeding modified precursors to wild-type organisms, and from directed evolution, which introduces random mutations into existing genes; instead, it operates at the level of pathway reassembly and domain swapping using defined genetic elements ^[4].