Fe3+-based nanovesicle mediated transferrin hijacking for glioblastoma stem cell tumoricidal treatment and postoperative recurrence inhibition

Glioblastoma (GBM) currently still faces the challenges of limited chemotherapy efficacy and high risk of postoperative recurrence, despite the implementation of multimodal treatment approaches. Glioblastoma stem cells (GSCs), characterized by multidirectional differentiation and potent tumorigenic potential, represent the "tumor seeds" contributing to these challenges. The therapeutic bottleneck for GSCs lies in the lack of drugs and treatment strategies that can simultaneously cross the blood-brain barrier (BBB) and target GSCs. In this study, we modified Fe³⁺ onto the surface of red blood cell nanovesicles (RNVs) to hijack transferrin (Tf) in the blood. The hijacked Tf recognizes Tf receptors highly expressed on brain microvascular endothelial cells and GSCs, thereby simultaneously enabling nanovesicle crossing of the BBB and targeting of GSCs. Fe³⁺ interacts with endogenous Fe²⁺ released from Hemoglobin in RNVs to create a feedback loop that amplifies Ferroptosis effects, enhancing the chemotherapeutic efficacy of temozolomide against GSCs. This Tf-hijacking nanovesicle enables GSC tumoricidal treatment and provides a novel approach for GBM postoperative recurrence inhibition.