Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM

Abstract

Background: Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe₃O₄-siPD-L1@M_-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM.

Results: Fe₃O₄-siPD-L1@M_-BV2 significantly increased the accumulation of siPD-L1 and Fe²⁺ in orthotopic drug-resistant GBM tissue in mice. Fe₃O₄-siPD-L1@M_-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe₃O₄-siPD-L1@M_-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe₃O₄-siPD-L1@M_-BV2.

Conclusion: The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe₃O₄-siPD-L1@M_-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice.

Keywords: Drug-resistant glioblastoma; Ferroptosis; Glioblastoma; Immunotherapy; Microglia; siPD-L1.