Metabolically‐Driven Active Targeting of Magnetic Nanoparticles Functionalized with Glucuronic Acid to Glioblastoma: Application to MRI‐Tracked Magnetic Hyperthermia Therapy

Abstract Glioblastoma continues to pose a major global health challenge due to its incurable nature. The need for new strategies to combat this devastating tumor is therefore paramount. Nanotechnology offers unique opportunities to develop innovative and more effective therapeutic approaches. However, most nanosystems developed to treat glioblastomas, especially those based on metallic nanoparticles (NPs), have proven unsuccessful due to their inability to efficiently target these tumors, which are particularly inaccessible due to the restrictions imposed by the blood‐brain tumor barrier (BBTB). Here, an innovative strategy is presented to efficiently target metallic NPs to glioblastomas through glucose transporters (GLUT) overexpressed on the endothelial cells of glioblastoma microvasculature, particularly GLUT1. Specifically, Iron Oxide Nanoparticles (IONPs) are functionalized with glucuronic acid to promote GLUT‐mediated transcytosis which is drastically boosted by inducing mild hypoglycemia. This metabolically‐driven active targeting strategy has yielded unprecedented efficacy in targeting metallic NPs to glioblastomas. Moreover, these IONPs, designed to act as magnetic hyperthermia (MH) mediators, are used to conduct a proof‐of‐concept preclinical study on MRI‐tracked MH therapy following intravenous administration, resulting in significant tumor growth delay. These findings demonstrate unparalleled efficiency in glioblastoma targeting and lay the ground for developing alternative therapeutic strategies to combat glioblastoma.