Triple-targeted artificial extracellular vesicles for enhanced glioma therapy via synergistic chemomagnetic penetration of the blood-brain barrier.

Malignant glioma remains one of the most aggressive and therapy-resistant brain tumors, with limited treatment options and a poor prognosis. Overcoming the blood-brain barrier (BBB) is a major challenge for effective drug delivery. Here, we developed a triple-targeted nanodelivery system, denoted BCNU-FeSeH@EVLF, which integrates magnetic guidance, chemotactic homing, and receptor-mediated transport for enhanced brain penetration and glioma treatment. The system consists of carmustine (BCNU)-loaded, hyaluronic acid-modified superparamagnetic Fe3O4 nanoparticles with a mesoporous selenium shell (FeSeH NPs), which are further encapsulated within lactoferrin-engineered extracellular vesicles (EVLF) derived from bone marrow mesenchymal stem cells. In vitro and in vivo studies demonstrated that BCNU-FeSeH@EVLF exhibited excellent BBB-crossing ability under magnetic field exposure, targeted accumulation in glioma tissues, and pH-responsive drug release within the tumor microenvironment. Selenium and BCNU act synergistically to induce reactive oxygen species generation, DNA damage, and apoptosis, leading to potent antiglioma efficacy. Importantly, the system showed high biocompatibility and negligible systemic toxicity. This work presents a robust and safe strategy for targeted glioma therapy via a multifunctional extracellular vesicle-based platform.