Dual-targeting zein janus nanoparticles reprogram tumor-associated macrophages for enhanced glioblastoma therapy

Glioblastoma (GBM) is one of the most malignant and lethal primary brain tumors, and the blood-brain barrier (BBB) poses a significant challenge to its treatment. In this study, disulfiram-loaded Zein Janus nanoparticles (Lf/M2pep@ZEN-DSF) were developed using the Pickering emulsion method for enhanced GBM therapy. Lactoferrin (Lf) was modified to one side of the Janus nanoparticles to facilitate BBB penetration and GBM targeting, while M2pep peptides were modified to the opposite side for targeting tumor-associated macrophages (TAMs). The results demonstrated that Lf/M2pep@ZEN-DSF effectively crossed the BBB and targeted brain tissues. Additionally, the Janus nanoparticles selectively targeted M2-polarized TAMs via M2pep and repolarized them into the M1 subtype for GBM therapy. Furthermore, the Janus nanoparticles significantly enhanced intracellular reactive oxygen species (ROS) generation in GBM cells. In vivo studies confirmed that the nanoparticles significantly increased drug accumulation in the brain and prolonged the survival of GBM-bearing mice. Immunohistochemical analysis revealed that Lf/M2pep@ZEN-DSF treatment induced M2-to-M1 TAM repolarization, effectively remodeling the tumor immune microenvironment. These findings collectively indicate that Lf/M2pep@ZEN-DSF is a promising nanomedicine with favorable biosafety for enhanced GBM treatment.