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

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials Pub Date : 2025-05-07 DOI:10.1016/j.biomaterials.2025.123387

Zheng Li , Guodong Ren , Xuewei Wang , Xiaowan Li , Lingwen Ding , Jianwei Zhu , Yajie Zhang , Chengwu Zhang , Jianhua Zou , Xiaoyuan Chen

{"title":"Tumor microenvironment responsive nano-PROTAC for BRD4 degradation enhanced cancer photo-immunotherapy","authors":"Zheng Li , Guodong Ren , Xuewei Wang , Xiaowan Li , Lingwen Ding , Jianwei Zhu , Yajie Zhang , Chengwu Zhang , Jianhua Zou , Xiaoyuan Chen","doi":"10.1016/j.biomaterials.2025.123387","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"322 ","pages":"Article 123387"},"PeriodicalIF":12.8000,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomaterials","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0142961225003060","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文本刊更多论文

肿瘤微环境响应纳米protac BRD4降解增强癌症光免疫治疗

蛋白水解靶向嵌合体（Proteolysis Targeting Chimeras， PROTAC）技术因其在靶向蛋白降解方面的优势而备受关注，在治疗恶性肿瘤方面具有很大的潜力。然而，PROTAC技术的固有缺陷阻碍了其临床应用。将纳米技术与PROTAC分子相结合，创造用于联合治疗的纳米PROTAC提供了一个很有前途的解决方案。在各种癌症治疗方法中，光疗因其已被证明的有效性和非侵入性而被认为是与特异性PROTACs结合的最佳选择。本文制备了一种由吲哚菁绿功能化聚乙二醇（PEG-ICG）光疗剂和BRD4降解剂（ARV-825）组成的纳米protac制剂（ARV@PEG-ICG），用于癌症光免疫治疗。在酸性肿瘤微环境（TME）的激活下，ARV@PEG-ICG纳米颗粒（NPs）会迅速分解，用于ARV的递送。PEG-ICG在激光照射下产生大量ROS，下调Bcl-xL的表达，诱导PARP的裂解，刺激细胞凋亡。此外，BRD4（一种转录辅助因子）的降解抑制了一氧化氮合酶（iNOS）的产生，从而提高了光疗效果。在4T1乳腺肿瘤模型中，死亡的4T1细胞释放肿瘤相关抗原（TAAs）作为免疫原性细胞死亡（ICD）诱导剂，促进DC成熟和T细胞活化，放大全身免疫应答。由于长期免疫反应的激活，远处肿瘤的生长也可以被抑制。总的来说，本研究旨在将典型的PROTAC与功能纳米材料结合，形成高性能的纳米PROTAC，用于PROTAC递送介导的癌症治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Biomaterials 工程技术-材料科学：生物材料

CiteScore

26.00

自引率

2.90%

发文量

565

审稿时长

46 days

期刊介绍： Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.