BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy

Shiman Lu; Zhaoqing Shi; Chendi Ding; Wenyan Wang; Weilang Zhang; Li Huang; Jiachan Lin; Xinpei Wang; Ran Luo; Xiaowei Zeng; Wenhu Zhou; Hongzhong Chen; Qiangsong Wang; Lin Mei

doi:10.1016/j.biomaterials.2025.123101

BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy

Biomaterials. 2025 Jan 10:317:123101. doi: 10.1016/j.biomaterials.2025.123101. Online ahead of print.

Authors

Shiman Lu¹, Zhaoqing Shi¹, Chendi Ding², Wenyan Wang³, Weilang Zhang⁴, Li Huang³, Jiachan Lin³, Xinpei Wang³, Ran Luo¹, Xiaowei Zeng³, Wenhu Zhou⁵, Hongzhong Chen⁶, Qiangsong Wang⁷, Lin Mei⁸

Affiliations

¹ State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.
² State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China. Electronic address: [email protected].
³ School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
⁴ State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China.
⁵ Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China; Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha, 410219, China.
⁶ School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China. Electronic address: [email protected].
⁷ State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China. Electronic address: [email protected].
⁸ State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China. Electronic address: [email protected].

PMID: 39799698
DOI: 10.1016/j.biomaterials.2025.123101

Abstract

The targeted protein degradation (TPD) strategy modulates tumor growth pathways by degrading proteins of interest (POIs) and has reshaped anti-tumor drug research and development. Recently, the emergence of photodegradation-targeting chimeras (PDTACs) and laser irradiation at specific sites enables precise spatiotemporal controllability of TPD. Capitalizing on the advances of PDTACs, herein, we report a nanoplatform for efficiently delivering PDTAC molecule for photodegradation of bromodomain-containing protein 4 (BRD4) proteins, the key activators of oncogenic transcription. The PDTAC molecule, named as PPa-JQ1, is synthesized through the covalent attachment of the BRD4-targeting ligand JQ1-acid, to the photosensitizer pyropheophorbide-a (PPa), utilizing a 1,6-hexanediamine linker. The PPa-JQ1 is further encapsulated by human serum albumin (HSA) to obtain the HSA@PPa-JQ1 nanoplatform, which facilitates targeted and efficacious delivery to melanoma lesions. Both in vitro and in vivo therapeutic outcomes demonstrate that HSA@PPa-JQ1 can efficiently generate reactive oxygen species (ROS) to degrade BRD4 upon light irradiation, which eventually induces tumor death. Our study represents the first case to validate the anti-tumor therapeutic efficacy of PDTACs by systemic administration, providing the foundation for further application of PDTACs.

Keywords: Albumin drug delivery systems; Bromodomain-containing protein 4; Melanoma therapy; Photodegradation-targeting chimeras; Targeted protein degradation.