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INTRODUCTION: Hyaluronic acid (HA) has been widely explored in cancer drug delivery due to its biocompatibility, biodegradability and excellent cargo properties. Recently, HA-based formulations have gained renewed interest thanks to the HA involvement in many CD44-overexpressing tumors, offering potential for active targeting, tumor microenvironment modulation, and immune response regulation. AREAS COVERED: This review explores the role of HA and its receptor in cancer progression and as a strategy for active therapeutic targeting. It also outlines the current status of HA-based formulations in clinical cancer therapy, emphasizing their clinical outcomes. The use of HA-drug conjugates, HA-based and -decorated nanoparticles (NPs), in chemotherapy, gene therapy, and theranostics is reviewed. Additionally, recent advancements in the role of HA in immune system modulation are discussed. All presented systems are herein evaluated for their ability to selectively target CD44-overexpressing cancer cells, with a focus on their in vivo biodistribution and therapeutic efficacy. EXPERT OPINION: Despite significant research, a few HA-based technologies have progressed to clinical trials, with only one showing promising results. Key challenges include high production costs, industrial scale-up feasibility, the need to preserve receptor recognition, and the off-target accumulation of HA in the liver and spleen barriers that must be addressed for successful clinical translation.
Andreana et al. (Mon,) studied this question.