Functionalized hyaluronic acid biomaterials-encouraged cancer immunotherapy through CD44-mediated targeting and cell surface engineering: A review

Abstract

Modified hyaluronic acid (HA) biomaterials have received considerable attention in recent years, especially in developing innovative therapeutic strategies for targeted disease interventions. HA serves to shield therapeutics from the physiological environment, while enabling safe delivery and promoting uptake into specific cells. As a hydrophilic chain polymer, HA is readily chemically modified into functional biomaterials for drug delivery and cancer immunotherapy. Due to its versatility, HA-based materials are also used in cell surface engineering, improving cell–cell interactions via HA-CD44 binding and triggering anti-tumor responses. This review examines HA's capacity to promote immune responses, recent advancements in HA-modified biomaterials, and the use of lipid-modified HA for cell surface engineering through CD44-mediated targeting. These approaches enhance cell–cell interactions and allow for localized tumor therapies while fostering anti-tumor immunity. Furthermore, the review covers various HA-based biomaterials including HA–drug conjugates, HA–lipids, HA-peptides, and HA–liposomes, their functions in modulating immune responses through HA-CD44, and perspectives on future directions in advancing cancer immunotherapy. © 2025 Elsevier B.V., All rights reserved.