Receptor‐Targeted Drug Delivery and the (Many) Problems We Know of: The Case of CD44 and Hyaluronic Acid

CD44 is best known for being the most common receptor of hyaluronic acid (HA). It is also a heterogeneous molecule: while its standard isoform (CD44s) is ubiquitously expressed, there are also a range of variants (CD44v), and both CD44s and CD44v undergo a variety of post‐translational modifications. The signaling roles and frequent overexpression of both CD44s and CD44v in cancer (e.g., in cancer initiating cells/cancer stem cells) has raised interest in them for diagnostic applications, but also—and most importantly for this review—as possible molecular targets in tumor therapy, with their endocytic character being a clear advantage for the intracellular release of payloads. In this area, the most popular approach employs HA‐based carriers. However, their rational design and therefore the success of HA‐based therapies are hampered by the rather limited understanding of not only the identity, but also the dynamic properties of CD44. In this review, the reader is exposed to the full breadth of the challenges that HA carriers currently face, which start at the CD44 post‐transcriptional and post‐translational heterogeneity, and also include the understanding of receptor clustering phenomena (influencing also HA avidity), as well as the evaluation of off‐target effects.