Receptor or Rhetoric? A Critical Review of Glucose Transporter-Targeting in Nanomedicine

Abstract

Despite the significant promise shown by nanoparticle-based diagnostics and therapies, there remain considerable challenges, especially concerning their targeting accuracy and specificity. This critical review explores glucose-conjugated nanoparticles (NPs) as more selective diagnostic and therapeutic tools for cancer treatment and drug transfer across the blood-brain barrier, with a particular focus on their interactions with glucose transporters (GLUTs) that are typically overexpressed in cancer and brain capillary endothelial cells. Although there are many reports of increased NP uptake upon glucose-functionalisation, the mechanistic basis for this targeting remains unclear. Here, we systematically evaluate the literature across inorganic, polymeric, liposomal, and micellar NP systems, examining how the nature of the linker and the conjugation strategy influence targeting. We place particular emphasis on the question whether convincing evidence for GLUT-mediated NP uptake has been provided, which is only possible using rigorous competition or inhibition control studies. We demonstrate that there is no such evidence for studies using direct conjugation of glucose, or conjugation via a short linker, to a solid NP. This is consistent with structural models placing the glucose-binding site deep within the transporter. However, conjugation at the end of sufficiently long and flexible linkers can enable genuine GLUT targeting. Similarly, the position and chemical nature of the glucose conjugation site needs to be considered carefully. Taken together, our review identifies a set of design principles that provide a rational foundation for future nanomedicine development. Studies incorporating these principles with stringent GLUT controls are more likely to generate transporter-specific platforms with genuine translational potential.