Dual molecularly imprinted nanocomposite with transferrin mediated glioma targeting and cholesterol exhaustion for synergistic cuproptosis/immune checkpoint blockade/immunogenic cell death

Effective therapies for Glioblastoma (GBM) are often challenging by virtue of the intracranial location of GBM tumors, molecular heterogeneity, high recurrence rate, and overall resistance to treatment. Therefore, we proposed the development of doxorubicin (DOX) loaded molecularly imprinted nanocomposites (DOX@MINPs-TRF/ChO) using transferrin (TRF) and cholesterol (ChO) as dual-template and Cu nanoparticles (Cu@BSNs) as a functional monomer for enhancing the treatment of GBM. The results showed that DOX@MINPs-TRF/ChO specifically and effectively adsorbed TRF in blood circulation and subsequently enhanced the brain tumor targeting capability <i>via</i> specific binding with transferrin receptors (TfR) highly expressed on the surface of GL261 cells. After intracellular internalization, DOX@MINPs-TRF/ChO conferred lysosome escape <i>via</i> proton sponge effects and demonstrated GSH responsive intracellular release of DOX and Cu²⁺ with the participation of disulfide bonds. As a result, it not only potentiated the synergistic induction of cuproptosis/apoptosis but also enhanced immunogenic cell death (ICD) effect. Furthermore, DOX@MINPs-TRF/ChO downregulated both PD-1 and PD-L1 expression through the specifical adsorption of ChO, remodeling the ChO metabolism axis in tumor regions and maintaining the immune-checkpoint blockade (ICB) effect. Collectively, DOX@MINPs-TRF/ChO induced synergistic cuproptosis/ICB/ICD and represented a potent strategy for enhancing treatment in GL261 glioma-bearing mice.