CD8a antibody-functionalized biomimetic red blood cell membrane ectosomes delivering C646 reverse CD8⁺ T Cell exhaustion via H3K18la histone delactylation in gastric cardia adenocarcinoma

The functional exhaustion of CD8+ T cells in the tumor microenvironment (TME) severely limits anti-tumor immunity in gastric cardia adenocarcinoma (GCA). Here, we developed CD8a antibody-functionalized biomimetic red blood cell membrane ectosomes (CD8a-NVEs) encapsulating the p300 inhibitor C646 to selectively target and reprogram exhausted CD8+ T cells. Single-cell RNA sequencing of human GCA tissues revealed lactate-driven epigenetic remodeling, characterized by elevated H3K18 lactylation (H3K18la) at the PDCD1 promoter, which correlated with impaired CD8⁺ T cell function. In vitro, C646 effectively reduced H3K18la, suppressed PDCD1 transcription, and restored effector molecule expression, including IFN-γ and GZMB. CD8a-NVEs@C646 exhibited superior targeting specificity, biocompatibility, and functional efficacy, markedly enhancing CD8⁺ T cell proliferation and cytotoxicity compared with free C646. In a humanized orthotopic GCA model, CD8a-NVEs@C646 significantly inhibited tumor growth, and its combination with anti–PD-1 therapy further enhanced T cell infiltration and tumor apoptosis. This biomimetic nanoplatform enables precise epigenetic reprogramming of tumor-infiltrating CD8⁺ T cells, overcoming lactate-induced histone modifications and reversing exhaustion. Collectively, these findings present a translational nanobiotechnology-based strategy to potentiate immunotherapy efficacy in GCA and potentially other malignancies driven by T cell dysfunction.