Combined Hyaluronic Acid Nanobioconjugates Impair CD44-Signaling for Effective Treatment Against Obesity: A Review of Comparison with Other Actors.

CD44, a key hyaluronic acid (HA) receptor, has emerged as a central mediator of adipose tissue inflammation, remodeling, and insulin resistance in obesity. Its overexpression in obese adipose depots promotes leukocyte infiltration, pro-inflammatory signaling, and extracellular matrix dysregulation processes that underlie metabolic dysfunction. This review explores the therapeutic relevance of targeting the HA-CD44 axis by synthesizing data primarily from preclinical studies, with emerging evidence from early clinical investigations. A narrative review methodology was employed to assess and compare therapeutic modalities, highlighting advances in molecular targeting, drug delivery systems, and metabolic interventions. We focus on two primary therapeutic classes: small molecules and nanobioconjugates. Small molecules, such as curcumin, metformin, and CD44 antagonists, offer systemic modulation and accessibility but are limited by their low tissue specificity and potential side effects. In contrast, HA-functionalized nanobioconjugates, including liposomes, PLGA nanoparticles, dendrimers, and exosomes, enable targeted delivery to adipose tissue, prolonged drug release, and reduced systemic toxicity. These nanosystems have demonstrated superior modulation of CD44 signaling, adipose inflammation, and glucose homeostasis in obesity models. Emerging strategies such as monoclonal antibodies, GLP-1 analogs, gene-editing tools (eg, CRISPR/Cas9), microbiome modulators, and brown adipose tissue (BAT) activators are also discussed. A comparative analysis indicates that nanobioconjugates offer the highest targeting precision, while small molecules remain advantageous in terms of cost and ease of administration. However, biologics and gene therapies face challenges related to delivery and scalability. Collectively, current evidence predominantly preclinical supports the HA-CD44 axis as a promising therapeutic target in obesity. Integrated approaches combining nanotechnology with molecular inhibitors and biologics could offer a multifaceted strategy for managing metabolic disease.