Hyaluronic acid-functionalized nanomedicines for CD44-receptors-mediated targeted cancer therapy: A review of selective targetability and biodistribution to tumor microenvironment.

Cancer is a leading cause of death globally, driven by late diagnoses, aggressive progression, and multidrug resistance (MDR). Advances in nanotechnology are tackling these challenges, paving the way for transformative cancer treatments. Hyaluronic acid (HA)-based nanoparticles (NPs) have emerged as promising platforms due to their biocompatibility, biodegradability, and natural targeting capabilities via CD44 (cluster of differentiation 44) receptors. Functionalizing NPs with HA enhances cellular uptake through CD44, improves pharmacokinetics, tumor localization, and anticancer efficacy while reducing systemic toxicity. This review provides a comprehensive overview of HA-based NPs, highlighting their potential to address limitations in cancer treatment and inspire further innovation. The targeting efficiency of HA-based NPs can be further optimized by integrating passive (e.g., PEGylation), active (e.g., ligand conjugation), and stimuli-responsive mechanisms (e.g., pH, redox, light, enzyme activity, and temperature sensitivity). These NPs also enable therapeutic combinations, such as co-delivery of chemotherapeutics with gene therapies (e.g., siRNA) and integration of photothermal and photodynamic therapies, alongside immune checkpoint inhibitors, amplifying therapeutic synergy. Despite promising preclinical results, challenges such as scalability, stability, long-term safety, ethical and regulatory hurdles, and high costs persist. Nonetheless, HA-based NPs represent a cutting-edge approach, combining biocompatibility, precision targeting, and multimodal functionality to combat cancer effectively, while mitigating side effects.