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瘤微环境响应的纳米-PROTAC用于BRD4降解增强癌症光免疫疗法

Zheng Li¹, Guodong Ren², Xuewei Wang²

¹Departments 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.

|May 9, 2025

概括

这项研究介绍了纳米PROTACs,将光疗和向蛋白质降解结合起来,用于癌症治疗. 这种新的方法通过触发免疫细胞死亡和全身免疫反应来提高治疗疗效.

科学领域:

生物医学工程生物医学工程
纳米技术纳米技术
癌症治疗癌症治疗

背景情况:

化向化体 (PROTAC) 提供针对癌症治疗的向蛋白质降解,但面临临临床翻译挑战.
将纳米技术与PROTAC (纳米-PROTAC) 集成,为联合癌症治疗提供了一个解决方案.
光疗是一种有效的非侵入性癌症治疗方法,非常适合与PROTACs集成.

研究的目的:

开发和评估一种新的纳米-PROTAC配方 (ARV@PEG-ICG) 用于联合光动力学疗法和向蛋白质降解在癌症治疗中.
研究ARV@PEG-ICG在诱导癌细胞亡和刺激抗瘤免疫反应方面的疗效.

主要方法:

制造ARV@PEG-ICG纳米颗粒,封装BRD4降解剂 (ARV-825) 和光疗剂 (绿色氨酸功能聚乙烯糖醇).
在酸性瘤微环境 (TME) 中对纳米粒子激活和在激光照射后产生ROS的评估.
在4T1乳腺瘤模型中评估BRD4降解,对Bcl-xL和iNOS的下游影响,以及诱导免疫细胞死亡 (ICD).

主要成果:

在激光照射下,ARV@PEG-ICG纳米颗粒有效地在TME中输送ARV-825并产生ROS,通过Bcl-xL下调和PARP裂变诱导细胞亡.
通过ARV-825降解BRD4,抑制了iNOS,增强了光疗疗效.
治疗诱导了ICD,促进了树突细胞成熟,T细胞激活和全身抗瘤免疫力,抑制了远部瘤的生长.

结论:

纳米PROTACs (ARV@PEG-ICG) 为PROTAC交付中介的癌症治疗提供了一个高性能平台.
光疗和通过纳米PROTACs向蛋白质降解的组合有效抑制瘤生长并增强抗瘤免疫力.
这一战略对通过创新的纳米医学方法推进癌症治疗具有重大前景.

关键词:

这就是BRD4D.免疫原性细胞死亡在Nano-PROTAC中使用.照相免疫疗法是一种照相疗法.有针对性的蛋白质降解降解.

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