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  3. Tumor microenvironment responsive nano-PROTAC for BRD4 degradation enhanced cancer photo-immunotherapy

Tumor microenvironment responsive nano-PROTAC for BRD4 degradation enhanced cancer photo-immunotherapy

  • Biomaterials. 2025 Nov:322:123387. doi: 10.1016/j.biomaterials.2025.123387.
Zheng Li 1,  Guodong Ren 2,  Xuewei Wang 2,  Xiaowan Li 2,  Lingwen Ding 3,  Jianwei Zhu 4,  Yajie Zhang 1,  Chengwu Zhang 5,  Jianhua Zou 6,  Xiaoyuan Chen 7
Affiliations

Affiliations

  • 1 Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore; Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
  • 2 School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, PR China.
  • 3 Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore.
  • 4 Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore; Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore; Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, 11 Biopolis Way, Helios, Singapore, 138667, Singapore.
  • 5 School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, PR China. Electronic address: chengwu_zhang@sxmu.edu.cn.
  • 6 Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore; Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore; Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, 11 Biopolis Way, Helios, Singapore, 138667, Singapore. Electronic address: zoujh-93@nus.edu.sg.
  • 7 Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore; Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore; Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore; Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, 11 Biopolis Way, Helios, Singapore, 138667, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore; Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, 117544, Singapore. Electronic address: chen.shawn@nus.edu.sg.
PMID: 40344878 DOI: 10.1016/j.biomaterials.2025.123387
Abstract

Proteolysis Targeting Chimeras (PROTAC) technology has garnered great attention due to its advantages in targeted protein degradation, promising its potential for treating malignant Cancer. Nevertheless, the inherent drawbacks of PROTAC technology hinder its clinical translation. The integration of nanotechnology with PROTAC molecules to create nano-PROTACs for combined therapy offers a promising solution. Among the various Cancer treatment methods, phototherapy is considered the optimal choice to integrate with specific PROTACs due to its proven effectiveness and non-invasive nature. Herein, a nano-PROTAC formulation (ARV@PEG-ICG) consisting of a phototherapeutic agent named indocyanine green functionalized polyethylene glycol (PEG-ICG) and a BRD4 Degrader (ARV-825) was fabricated for Cancer photo-immunotherapy. Activated by acidic tumor microenvironment (TME), ARV@PEG-ICG nanoparticles (NPs) will decompose rapidly for ARV delivery. PEG-ICG generated abundant ROS with laser irradiation, downregulating the expression of Bcl-xL and inducing the cleavage of PARP to stimulate cell Apoptosis. Furthermore, the degradation of BRD4, a transcriptional cofactor, inhibited nitric oxide synthase (iNOS) generation to improve phototherapeutic efficacy. In a 4T1 breast tumor model, dying 4T1 cells released tumor associated antigens (TAAs) to serve as the immunogenic cell death (ICD) inducer, facilitating DC maturation and T cell activation and amplifying systemic immune response. The distant tumor growth can also be inhibited due to the activation of long-term immune response. Overall, the current study aims to combine typical PROTAC with functional nanomaterials to form nano-PROTAC with high performance for PROTAC delivery mediated Cancer treatment.

Keywords

BRD4; Immunogenic cell death; Nano-PROTAC; Photo-immunotherapy; Targeted protein degradation.

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