The evolving logic of biocatalyzed nucleic acid synthesis

Enzymes are typically understood as agents of biological fidelity, but this characterization obscures their growing role as programmable catalysts for molecular invention. In this review, we examine the emerging logic of biocatalyzed nucleic acid synthesis beyond the genetic canon, organizing recent progress into two complementary paradigms: template-dependent and template-independent enzymatic construction. Rather than cataloguing individual modifications, we emphasize the organizing principles that enable enzymes to operate outside their evolutionary remit, including the roles of templating, substrate modularity, steric gating, and reaction cycling in preserving sequence information while expanding chemical scope. We highlight how these principles enable the synthesis of therapeutically relevant oligonucleotides at scale, support the exploration of alternative genetic systems, and allow chemical functionality to be encoded directly into informational polymers.