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

Solid tumor immunotherapy is often constrained by CD8⁺ T cell exhaustion, destabilized immunological synapse formation, and aberrant PD-1 activation; however, the underlying epigenetic transcriptional regulation and actionable targets remain incompletely defined. Therefore, we developed the CD8⁺ T cell membrane-coated GSK3β inhibitor-loaded cerium oxide (CeO₂) nanozyme (CD8m-CeO₂@GSK3i) to enable immunological synapse-targeted delivery of a GSK3β inhibitor and thereby remodel the function of exhausted CD8⁺ T cells. The nano-system was evaluated through characterization, multi-enzyme activity assays, and reactive oxygen species (ROS)-responsive drug-release testing, and was further investigated using mitochondrial metabolism profiling, live-cell imaging, flow cytometry, confocal microscopy, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq), RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), and co-immunoprecipitation (Co-IP), before in vivo efficacy was evaluated in B16F10 and MC38 mouse models. The nano-system restored mitochondrial metabolism, Ca²⁺ signaling, and immunological synapse architecture and enhanced CD8⁺ T cell killing and secretory functions. Treatment also reduced PD-1 transcription, attenuated exhaustion-related phenotypes, and altered the GSK3β-TIPE-β-catenin-PD-1 regulatory axis. Combining the nano-system with PD-1 blockade further strengthened antitumor effects. Collectively, this work establishes a nano-intervention strategy for improving immunotherapy responses in solid tumors.