Engineering Strategies for Hyaluronan Synthesis: A Review of Enzyme Modifications, Strain Selection, and Molecular Weight Control

Hyaluronan is a biopolymer with significant biological and commercial importance, particularly due to its applications in medical, cosmetic, and tissue engineering fields. The molecular weight of HA is a key factor that influences its biological function, ranging from anti-inflammatory properties in high-molecular-weight HA to pro-inflammatory effects in low-molecular-weight HA. Recent advancements in protein and strain engineering have enabled precise control of the molecular weight of hyaluronan by manipulating both hyaluronan synthase enzyme variants and the host microbial strains used in hyaluronan production. Strain engineering, through genetic modification and metabolic pathway optimization, enhances the efficiency and yield of hyaluronan with defined molecular properties. Despite progress in industrial-scale hyaluronan production, achieving monodisperse hyaluronan with well-defined molecular weights remains a challenge. This review explores the current breakthroughs in enzyme and strain engineering strategies to optimize hyaluronan synthase enzyme activity and microbial host systems, aiming to produce size-controlled hyaluronan polymers with improved therapeutic efficacy. We discuss the role of specific hyaluronan synthase enzyme mutations and truncations, strain selection, and metabolic engineering, as well as the potential of in vitro cell-free systems for producing hyaluronan with tailored molecular properties for advanced biomedical applications.