Tumor exosome-based drug delivery system targeting ferroptosis and apoptosis for glioblastoma therapy.

Temozolomide (TMZ) is a first-line chemotherapy drug to treat glioblastoma (GBM), but still encounters blood-brain barrier (BBB), and chemotherapy resistance. To address these issues, sensible combination therapy of TMZ with other novel therapeutic techniques is required. Herein, we developed a tumor cell exosome membrane (EM) based drug delivery platform (EMNPs@TMZ) for encapsulating reactive oxygen species (ROS) responsive fucoidan (Fuc) nanoparticles (FNPs). EMNPs@TMZ system can co-deliver TMZ and luteolin (Lut) for the combined targeting apoptosis and ferroptosis. Interestingly, Lut can induce ferroptosis by inhibiting Nrf2 expression, and also inhibit DNA repair through Wnt/β-catenin, promoting TMZ induced cell apoptosis. Notably, this nanoparticle drug delivery system exhibits a dual-targeting effect on tumors, significantly inhibiting GBM growth and improving survival in mouse models. Treatment with these nanoparticles did not cause significant side effects, particularly in orthotopic patient-derived xenograft (PDX) models. This biomimetic nanoparticle provides a promising strategy for ferroptosis combination chemotherapy for GBM therapy.