Glycosaminoglycan-Based CD44-Targeted Nanoparticles for Cancer Therapy: Biological Barriers and Barrier-Informed Design Strategies

Abstract

Nanoparticle (NP)-based drug delivery has been explored to improve the therapeutic index of anticancer agents by enhancing tumor accumulation and reducing systemic toxicity. Among active targeting approaches, cluster of differentiation 44 (CD44) has attracted attention because of its overexpression in tumor cells and tumor-associated endothelial cells and its involvement in tumor progression and therapeutic resistance. Hyaluronic acid (HA) and other glycosaminoglycan (GAG)-based nanocarriers have been developed to exploit CD44-mediated tumor targeting and cellular uptake. However, the in vivo performance of CD44-targeted NPs remains variable because of barriers such as systemic clearance, heterogeneous tumor vasculature and stroma, limited receptor accessibility, competition with endogenous ligands, and inefficient intracellular trafficking or payload release. This Letter summarizes advances in CD44-targeted NP delivery, focusing on barriers at systemic, tumor tissue, and cellular levels. We discuss barrier-informed strategies to optimize ligand presentation, improve penetration, promote intracellular payload release, and highlight translational challenges and opportunities for CD44-targeted nanomedicines.