Hyaluronic acid-based nanocarriers for cancer therapy: molecular design, biointerface mechanisms, and translational challenges

Abstract

Hyaluronic acid (HA) has emerged as a versatile structural material and targeting ligand within cancer drug delivery systems and nanomedicine applications, owing to its biodegradability, tunable chemistry, and strong affinity for CD44 and related receptors. This review examines studies published from 2019 to 2026, with emphasis on high-quality research in leading journals, and connects the structural parameters of HA with quantitative drug delivery efficiency and therapeutic performance. The major HA-based carrier systems, including micelles, liposomes, polymeric nanoparticles, metal–organic frameworks, and electrospun fiber systems, are critically analyzed in relation to HA molecular weight, degree of substitution, and ligand density, as well as their effects on hydrodynamic size, zeta potential, colloidal stability, and cellular uptake. Across these studies, the most effective designs generally feature nanoscale dimensions that balance circulation and tumor penetration while maintaining near-neutral or slightly negative surface potentials to minimize nonspecific interactions, highlighting the importance of rational physicochemical design for improving therapeutic performance. Quantitative models of drug release, together with in vitro potency indices such as half-maximal inhibitory concentration (IC50) and combination index, as well as in vivo pharmacokinetic and efficacy indicators including half-life, area under the curve (AUC), and tumor-to-organ ratio, demonstrate how the configuration of HA influences therapeutic selectivity and systemic safety. To improve the rigor and reproducibility of future studies, this review further proposes a concise reporting framework integrating materials characterization, biological evaluation, and animal experiments, while highlighting the current limitations in standardization and cross-study comparability. In conclusion, this review summarizes the current design principles of HA-based nanocarriers while critically discussing the remaining challenges, including CD44 heterogeneity, microenvironmental competition, and the lack of standardized evaluation strategies. Together, these perspectives provide practical guidance for the rational design, comparative evaluation, and clinical translation of next-generation HA-based nanocarriers.