CD8⁺ T cell membrane-camouflaged cerium oxide nanozyme enables targeted delivery of a Gsk3β inhibitor to the immunological synapse, reconstructing immunological synapse homeostasis and alleviating limited immunotherapeutic responses in solid tumors by decoupling the β-Catenin-TIPE-PD-1 enhancer complex
Preclinical evaluation reveals that targeted nanozyme delivery of a GSK3β inhibitor restores T cell function in solid tumors, suggesting a viable strategy to enhance immunotherapy efficacy.
Key Points
To investigate whether a biomimetic cerium oxide nanozyme targeted to the immunological synapse can reverse CD8⁺ T cell exhaustion and enhance antitumor immunotherapy in solid tumors.
Engineered CD8⁺ T cell membrane-coated cerium oxide nanozymes loaded with a GSK3β inhibitor (CD8m-CeO₂@GSK3i) featuring multi-enzyme catalytic activity and ROS-responsive drug release.
Profiled mechanistic actions via mitochondrial metabolic assays, live-cell imaging, scATAC-seq, bulk and single-cell RNA-seq, ChIP-qPCR, and Co-IP.
Evaluated in vivo antitumor efficacy, immune synapse remodeling, and combination treatment with anti-PD-1 blockade in B16F10 melanoma and MC38 colon cancer mouse models.
CD8m-CeO₂@GSK3i remodeled immunological synapse structure, restored mitochondrial metabolism and Ca²⁺ signaling, and augmented CD8⁺ T cell cytotoxicity and secretion.
Nanoparticle delivery decoupled the GSK3β-TIPE-β-catenin-PD-1 enhancer complex, repressing PD-1 transcription and reversing exhaustion-associated phenotypes.
Combining the nano-system with PD-1 blockade significantly boosted antitumor immune responses and tumor inhibition compared to single-agent treatments in vivo.