Copper-coordination driven brain-targeting nanoassembly for efficient glioblastoma multiforme immunotherapy by cuproptosis-mediated tumor immune microenvironment reprogramming

Copper-coordination driven brain-targeting nanoassembly for efficient glioblastoma multiforme immunotherapy by cuproptosis-mediated tumor immune microenvironment reprogramming

Blog Article

Abstract Limited drug accumulation and an immunosuppressive microenvironment are the major bottlenecks in the treatment of glioblastoma multiforme (GBM).Herein, we report a copper-coordination driven brain-targeting nanoassembly (TCe6@Cu/TP5 NPs) for Baby Tee site-specific delivery of therapeutic agents and efficient immunotherapy by activating the cGAS-STING pathway and downregulating the expression of PD-L1.To achieve this, the mitochondria-targeting triphenylphosphorus (TPP) was linked to photosensitizer Chlorin e6 (Ce6) to form TPP-Ce6 (TCe6), which was then self-assembled with copper ions and thymopentin (TP5) to obtain TCe6@Cu/TP5 NPs.This nanoassembly effectively accumulated in tumor sites through the copper transport mechanism.Meanwhile, TCe6@Cu/TP5 could induce mitochondrial impairment by photodynamic therapy (PDT) mediated reactive oxygen species (ROS) accumulation and Cu2+ triggered cuproptosis, resulting in evoking the AMP-activated protein kinase (AMPK) pathway to degrade PD-L1, and activating the cGAS-STING pathway to enhance anti-tumor immunity.

Moreover, TP5 significantly promoted the proliferation and differentiation of dendritic cells (DCs) and T home lymphocytes to further amplify the cancer immunity cycle.Collectively, our TCe6@Cu/TP5 NPs effectively facilitate drug accumulation and activate systemic antitumor immunity in vitro and in vivo, providing an innovative solution across the BBB that potentiates GBM immunotherapy.Graphical Abstract.