Ultrasound- and Magnet-Enhanced Blood-Brain Barrier Transport for Self-Augmented Piezo-Fenton Glioblastoma Therapy

Glioblastoma (GBM) remains the most aggressive primary brain tumor, with therapeutic efficacy constrained by the blood-brain barrier (BBB) that restricts targeted drug delivery. Although certain therapeutics successfully traverse the BBB, elevated interstitial pressure within tumors continues to compromise intratumoral penetration. To enhance intratumoral delivery of GBM, a dual-responsive nanodrug is constructed by incorporating piezoelectric BaTiO₃ (BTO) nanoparticles with magnetic Fe₃O₄. Ultrasound induces a temporary opening of the BBB, facilitating subsequent targeted delivery of the nanodrug to the GBM site under magnetic guidance. Under ultrasound stimulation, the nanoparticles then conduct a piezocatalytic water splitting within tumor interstitium, reducing fluid pressure and enabling drug penetration into the tumor core region. After deeply penetrating into the tumor, the nanodrugs generate electrons through piezocatalysis and then reduce Fe³⁺ to Fe²⁺. The sustainable generated Fe²⁺ initiates a piezo-Fenton coupled catalytic system that produces abundant reactive oxygen species (ROS) for oxidative cell stress. This study develops a 3-step strategy for ultrasound-/magnet- GBM navigation and penetration, optimizing drug delivery mode in GBM therapy. Moreover, the on-site piezo-Fenton coupled catalysis achieves continuous ROS regeneration and iron species recycling, thereby effectively eradicating GBM.