Hyaluronic acid: A powerful targeting ligand for cancer therapy-A review

Traditional cancer therapies are limited by poor selectivity and systemic toxicity, highlighting the need for active targeting strategies to achieve precise treatment. Hyaluronic acid (HA), a naturally occurring glycosaminoglycan, has emerged as a powerful ligand for precision cancer therapy owing to its excellent biocompatibility, biodegradability, ease of modification, non-immunogenicity, and specific binding affinity to the cluster determinant 44 (CD44) receptors. This review summarizes the key physicochemical properties of HA and the molecular mechanisms of HA-CD44 recognition, emphasizing how the HA molecular weight influences its binding affinity to CD44. We further discuss the diverse chemical modification strategies on carboxyl, hydroxyl, and N-acetyl groups of HA and highlight how these modifications affect CD44 binding affinity. Moreover, the unique features of the tumor microenvironment (TME) are also highlighted to guide the rational design of stimuli-responsive HA-based nanoplatforms. A central focus is placed on the recent progress in the development of various HA-based nanoplatforms, focusing on their role in reducing off-target effects and enhancing therapeutic efficacy. The challenges of achieving clinical translation of existing HA-based nanoplatforms and future directions in the field are also discussed. By integrating design principles with biological complexity and translational considerations, this review provides practical insights to guide the rational development of next-generation HA-based nanomedicines for precision cancer therapy.