Uti Daniel Ejim, Omang Wilson Achu, Alum Esther Ugo, Ugwu Okechukwu Paul-Chima, Wokoma Margaret Amieibi, Oplekwu Rowland Inalegwu, Atangwho Item Justin, Egbung Godwin Eneji
Department of Research and Publications, Kampala International University, Kampala, Uganda.
Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, Federal University of Health Sciences, Otukpo, Benue State, Nigeria.
Int J Nanomedicine. 2025 Aug 21;20:10101-10126. doi: 10.2147/IJN.S529250. eCollection 2025.
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.
CD44是一种关键的透明质酸（HA）受体，已成为肥胖症中脂肪组织炎症、重塑和胰岛素抵抗的核心介质。它在肥胖脂肪库中的过度表达促进了白细胞浸润、促炎信号传导以及构成代谢功能障碍基础的细胞外基质失调过程。本综述通过综合主要来自临床前研究的数据以及早期临床研究的新证据，探讨了靶向HA-CD44轴的治疗意义。采用叙述性综述方法来评估和比较治疗方式，突出分子靶向、药物递送系统和代谢干预方面的进展。我们重点关注两类主要的治疗方法：小分子和纳米生物缀合物。小分子，如姜黄素、二甲双胍和CD44拮抗剂，可实现全身调节且易于获取，但受限于其低组织特异性和潜在的副作用。相比之下，HA功能化的纳米生物缀合物，包括脂质体、聚乳酸-羟基乙酸共聚物纳米颗粒、树枝状大分子和外泌体，能够靶向递送至脂肪组织，延长药物释放，并降低全身毒性。这些纳米系统在肥胖模型中已显示出对CD44信号传导、脂肪炎症和葡萄糖稳态的卓越调节作用。还讨论了单克隆抗体、胰高血糖素样肽-1（GLP-1）类似物、基因编辑工具（如CRISPR/Cas9）、微生物群调节剂和棕色脂肪组织（BAT）激活剂等新兴策略。比较分析表明，纳米生物缀合物具有最高的靶向精度，而小分子在成本和给药便利性方面仍具有优势。然而，生物制剂和基因疗法面临与递送和可扩展性相关的挑战。总体而言，目前主要来自临床前的证据支持HA-CD44轴作为肥胖症中一个有前景的治疗靶点。将纳米技术与分子抑制剂和生物制剂相结合的综合方法可为管理代谢疾病提供多方面的策略。
