Brain-Targeting Nanoplatform Repurposing Silymarin for Enhanced GBM Immunotherapy via Synergistic Mitochondrial Suppression

Glioblastoma (GBM), a highly malignant central nervous system tumor, poses a major therapeutic challenge due to the poor blood-brain barrier (BBB) permeability and an immunosuppressive tumor microenvironment. Notably, silymarin, a natural compound known for its anti-inflammatory and liver-protective properties, has emerged as a promising candidate for GBM immunotherapy through the inhibition of glycolysis and induction of mitochondrial damage. In this study, we developed a silymarin-repurposed, site-specific delivery photo-chemotherapy nanoplatform, designed to synergistically suppress mitochondria for efficient GBM immunotherapy. The platform utilizes a self-assembly strategy incorporating brain-targeted lactoferrin (LF), triphenylphosphine-modified chlorin e6 (TCe6), and silymarin. Mechanistically, LF facilitates targeted binding to low-density lipoprotein receptor-related protein-1 (LRP1), enabling BBB penetration and inducing mitochondrial dysfunction in GBM cells through TCe6-mediated intracellular reactive oxygen species (ROS) generation and silymarin-induced glycolysis suppression. This mitochondrial dysfunction triggers the activation of the AMPK pathway, leading to the degradation of programmed cell death ligand-1 (PD-L1) and the activation of the cGAS-STING pathway, thereby enhancing the anti-tumor immune response. As anticipated, this nanoplatform significantly improves BBB permeability and antitumor immunity, providing an innovative drug repurposing strategy for effective GBM immunotherapy.