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

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

  • J Nanobiotechnology. 2026 Jan 29;24(1):156. doi: 10.1186/s12951-025-03957-z.
Zheng Xiang # 1,  Xinxin Zhang # 2 3,  Xinlei Liu 1,  Xiaohu Lv 1,  Yubo Hu 1,  Chi Zhang 1,  Chunlei Zou 1,  Anqi Wang 3 4,  Bo Zhang 2 3,  Wei Wang 5,  Guodong Cao 6,  Jianguang Jia 7 8
Affiliations

Affiliations

  • 1 Department of Oncology, The Second Affiliated Hospital of Bengbu Medical University, No. 633 Longhua Road, Huaishang District, 233000, Bengbu, China.
  • 2 Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, 201800, China.
  • 3 Shanghai Key Laboratory for Cancer Systems Regulation and Clinical Translation, Shanghai, 201800, China.
  • 4 Department of General Practice Medicine, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, 201800, China.
  • 5 Department of Oncology, The Second Affiliated Hospital of Bengbu Medical University, No. 633 Longhua Road, Huaishang District, 233000, Bengbu, China. [email protected].
  • 6 Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Anhui Province, 230000, Hefei, China. [email protected].
  • 7 Department of Oncology, The Second Affiliated Hospital of Bengbu Medical University, No. 633 Longhua Road, Huaishang District, 233000, Bengbu, China. [email protected].
  • 8 Department of Oncology, the First Affiliated Hospital of Bengbu Medical University, No. 287, Changhuai Road, Anhui Province, 233004, Bengbu, China. [email protected].
  • # Contributed equally.
PMID: 41612336 DOI: 10.1186/s12951-025-03957-z
Abstract

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.

Keywords

C646; Gastric cardia adenocarcinoma; H3K18la; Programmed cell death protein 1; Red blood cell membrane-derived ectosomes.

Figures
Products