Self-assembled genistein nanoparticles suppress the epithelial-mesenchymal transition in glioblastoma by targeting MMP9.

Glioblastoma (GBM) is the most prevalent and aggressive primary malignant brain tumor in adults, known for its poor prognosis and resistance to conventional treatments. The blood-brain barrier (BBB) presents a significant challenge in delivering effective treatments. In this study, we developed a carrier-free, self-assembled nanosystem using genistein (GE), a naturally occurring isoflavone, to enhance therapeutic delivery across the BBB. GE nanoparticles (GE NPs) were synthesized via solvent emulsification evaporation, in uniform spherical particles (∼180 nm), stabilized by hydrogen bonding and π-π interactions. The GE NPs demonstrated optimal physicochemical properties, including stability, high BBB permeability, prolonged circulation time. In vitro studies revealed that GE NPs inhibited GBM cell proliferation, induced apoptosis and suppressed epithelial-mesenchymal transition (EMT) by promoting the degradation of MMP9. In vivo, GE NPs significantly reduced tumor growth and extended survival in an orthotopic GBM mouse model, outperforming temozolomide treatment. Mechanistic analysis indicated that GE NPs inhibited the degradation of the extracellular matrix by targeting the catalytic domain of MMP9, thereby effectively suppressing the EMT of GBM. This research highlights the potential of GE NPs as a novel therapeutic approach for GBM, addressing drug delivery challenges while improving anti-tumor efficacy. Further optimization for enhanced tumor retention and exploration of combination therapies may improve clinical outcomes (Graphical Abstract).