Copper-coordination driven brain-targeting nanoassembly for efficient glioblastoma multiforme immunotherapy by cuproptosis-mediated tumor immune microenvironment reprogramming
Yang Chen, Hailong Tian, Xiaodian Zhang, Edouard C. Nice, Canhua Huang, Haiyuan Zhang, Shaojiang Zheng
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 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 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.