Targeting CD44-Hyaluronic Acid Signalling in Obesity Treatment: Insights from Small Molecules and Nanobioconjugates

Obesity is a complex metabolic disorder associated with chronic low-grade inflammation, insulin resistance, and heightened risk of comorbidities such as cardiovascular diseases and type 2 diabetes mellitus (T2DM). The Cluster of Differentiation 44 (CD44), a transmembrane glycoprotein, interacts with hyaluronic acid (HA), a major extracellular matrix (ECM) component, to regulate adipogenesis, immune cell infiltration, and metabolic dysfunction. Dysregulation of the CD44-HA signalling axis promotes adipose tissue hypertrophy, macrophage infiltration, and activation of pro-inflammatory pathways, including nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), which further aggravate metabolic disturbances. This review provides a comprehensive analysis of CD44-HA signalling in the pathophysiology of obesity and evaluates therapeutic strategies targeting this axis. Small-molecule inhibitors, such as CD44 antagonists and hyaluronan biosynthesis modulators (eg, 4-methylumbelliferone), offer advantages in synthesis, bioavailability, and cost-effectiveness, but face challenges related to limited specificity, systemic toxicity, and potential resistance. In contrast, Nanobioconjugates engineered nanoparticles conjugated with biomolecules such as HA enable targeted delivery to CD44-overexpressing adipose tissues, enhance therapeutic efficacy, prolong drug release, and minimize off-target effects. Examples include lipid-based nanoparticles, polymer-based nanocarriers, and HA-functionalized systems, all of which show promise in preclinical models of obesity. Comparative analysis underscores the superior specificity and bioavailability of nanobioconjugates, though issues of large-scale production, immunogenicity, and regulatory approval remain. Combining nanobioconjugates with small molecules may optimize treatment outcomes by leveraging synergistic mechanisms. Emerging strategies including high-affinity HA ligands, monoclonal antibodies, RNA-based therapeutics, and artificial intelligence (AI) guided drug design, offering new opportunities for precision obesity management. Future directions highlight the importance of personalized and combinatorial therapies, supported by biomarker profiling and gene editing technologies such as CRISPR, to overcome current limitations in CD44-HA-targeted interventions.