Advancements in Hyaluronic Acid Synthetic Methodologies and Their Translational Relevance.

Hyaluronic acid (HA) is a linear and nonsulfated glycosaminoglycan of interest because of its complex biological activity and therapeutic potential. For example, HA targets CD44 and RHAMM receptors, which are overexpressed on the surface of numerous cancer cell types, and thus HA is widely investigated for delivery of potent anticancer agents. However, HA-containing formulations for therapeutics have had little clinical success. The challenge lies in the heterogeneity of biologically sourced HA, which results in batch-to-batch variation and inconsistent biological activity. Consequently, developing methodologies to access well-defined HA with narrow dispersity is the key to advancement. In this Review, we discuss the biological role of HA within cancer and cancer immune regulation and extend the discussion to the importance of HA in both osteoarthritis and rheumatoid arthritis. We then summarize both synthetic and enzymatic methodologies for accessing HA and its derivatives including HA oligosaccharides, HA polymeric derivatives, HA conjugates, and HA-based nanoparticles and hydrogels with an emphasis on biomaterial reports from the past decade (2015-2025). This Review highlights the biological relevance of HA and the critical need for successful methodologies and therapeutic designs to achieve clinical translation culminating in impactful patient outcomes.