Therapeutic Reprogramming of Glioblastoma Phenotypic States Using Multifunctional Heparin Nanoparticles

Abstract

Glioblastomas (GB) are the most common and deadly primary malignant brain tumors due to their infiltrative growth and resistance to conventional therapies. GB cell plasticity and differentiation into drug-resistant mesenchymal-like (MES) states protect tumors from conventional treatments. This study introduces a novel precision medicine approach employing heparin-based nanoparticles (HP-NPs) engineered to cross the blood-brain barrier and target MES-like glioma stem cells (GSCs). Encapsulating doxorubicin (DOX) in HP-NPs reduces drug-mediated complement and coagulation cascades, enhancing hemocompatibility in human whole blood. In vitro, HP-NPs demonstrate efficient uptake by patient-derived GSCs. Preclinical evaluations in patient avatars indicate plain HP-NPs outperform DOX-loaded HP-NPs in reducing GB progression. Transcriptomic studies show HP-NPs downregulate heparin-binding epidermal growth factor (HBEGF), shifting MES GSCs into less plastic astroglial-like cells, impairing tumorigenesis. HP-NPs are well-tolerated and safe at therapeutic doses in healthy rats, offering a promising new paradigm in anticancer therapy to overcome GB recurrence and improve therapeutic outcomes.