β-Ketoenamine covalent organic framework nanoplatform combined with immune checkpoint blockade via photodynamic immunotherapy inhibit glioblastoma progression

Tengfeng Yan; Qiuye Liao; Zhihao Chen; Yang Xu; Wenping Zhu; Ping Hu; Si Zhang; Yanze Wu; Lei Shu; Junzhe Liu; Min Luo; Hongxin Shu; Yilei Sheng; Li Wang; Chun Xu; Chang Lei; Hongming Wang; Qingsong Ye; Li Yang; Xingen Zhu

doi:10.1016/j.bioactmat.2024.10.029

β-Ketoenamine covalent organic framework nanoplatform combined with immune checkpoint blockade via photodynamic immunotherapy inhibit glioblastoma progression

Bioact Mater. 2024 Nov 7:44:531-543. doi: 10.1016/j.bioactmat.2024.10.029. eCollection 2025 Feb.

Authors

Tengfeng Yan^{1

2

3

4}, Qiuye Liao¹, Zhihao Chen¹, Yang Xu⁵, Wenping Zhu^{3

4}, Ping Hu¹, Si Zhang¹, Yanze Wu¹, Lei Shu¹, Junzhe Liu¹, Min Luo¹, Hongxin Shu¹, Yilei Sheng¹, Li Wang⁶, Chun Xu^{7

8}, Chang Lei^{8

9}, Hongming Wang¹⁰, Qingsong Ye¹¹, Li Yang^{3

4}, Xingen Zhu^{1

2

3

4}

Affiliations

¹ Department of Neurosurgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330000, China.
² Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, Jiangxi Province, 330000, China.
³ JXHC Key Laboratory of Neurological Medicine, Nanchang, Jiangxi Province, 330000, China.
⁴ Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi Province, 330000, China.
⁵ Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China.
⁶ College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99 Ziyang Road, Nanchang, 330022, China.
⁷ Sydney Dental School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
⁸ Charles Perkins Centre, The University of Sydney, Camperdown, NSW, 2006, Australia.
⁹ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
¹⁰ College of Chemistry and Chemical Engineering and Jiangxi Provincial Key Laboratory of Functional Crystalline Materials Chemistry Nanchang University, Nanchang, 330031, China.
¹¹ Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan University, 430060, Wuhan, China.

Abstract

The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma (GBM) patients. The observed upregulation of O-GlcNAc glycolysis in tumors may contribute to the stabilization of endogenous PD-L1 protein, facilitating tumor immune evasion. This study presents a pH-adapted excited state intramolecular proton transfer (ESIPT)-isomerized β-ketoamide-based covalent organic framework (COF) nanoplatform (denoted as OT@COF-RVG). Temozolomide (TMZ) and OSMI-4 (O-GlcNAc transferase inhibitor) were integrated into COF cavities, then modified on the surface with polyethylene glycol and the rabies virus peptide RVG-29, showing potential for sensitizing TMZ chemotherapy and initiating photodynamic therapy (PDT). By inhibiting O-GlcNAc and promoting lysosomal degradation of PD-L1, OT@COF-RVG enhanced the effectiveness of immune checkpoint blockade (ICB) therapy. Additionally, treatment with OT@COF-RVG led to a notable elevation in reactive oxygen species (ROS) levels, thereby re-establishing an immunostimulatory state, inducing immunogenic cell death (ICD). In summary, our research unveiled a correlation between O-GlcNAc in GBM and the evasion of immune responses by tumors, while showcasing the potential of OT@COF-RVG in reshaping the immunosuppressive microenvironment of GBM and offering a more effective approach to immunotherapy in clinical settings.

Keywords: Checkpoint blockade; Covalent organic framework; Drug delivery; Glioblastoma; Photodynamic immunotherapy.