Targeting the Cluster of Differentiation 44–Hyaluronic Acid Axis in Triple-Negative Breast Cancer: Design and Therapeutic Applications of Hyaluronic Acid-Based Nanocarriers

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by the absence of estrogen receptors, progesterone receptors, human epidermal growth factor receptor 2, notable heterogeneity, early metastasis, and a swift development of resistance to chemotherapy. Hyaluronic acid-based nanocarriers represent a logical approach to addressing these challenges by utilizing the cluster of differentiation 44 (CD44)–hyaluronic acid (HA) axis, which enables the targeted delivery of chemotherapeutics, nucleic acids, and immunomodulators to TNBC cells and cancer stem cells. This review initially explains the biology of TNBC and highlights the pivotal role of CD44 in the process of epithelial–mesenchymal transition, metastasis, and treatment failure, thus providing a mechanistic rationale for HA-mediated targeting. This review further analyzes the design principles and structural architectures of HA-based nanocarriers, including HA-polymeric nanoparticles, liposomes, micelles, hydrogels, and prodrug conjugates, and discusses their relevance in addressing key therapeutic challenges in TNBC. Particular emphasis is placed on overcoming poor responsiveness to chemotherapy, multidrug resistance, cancer stemness, and the immunosuppressive tumor microenvironment. In addition, the translational challenges associated with HA-based nanomedicines for TNBC are critically evaluated, with the aim of outlining practical design guidelines and highlighting promising future research directions for effective clinical translation.