Polymer-PARPi Conjugates Delivering USP1i for Maximizing Synthetic Lethality to Stimulate STING Pathway in High-Grade Serous Ovarian Cancer.

IF 26.8 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Advanced Materials Pub Date : 2025-09-19 DOI:10.1002/adma.202512962

He Zhang,Yi Sun,Lingpu Zhang,Meifang Shen,Xiaowei Tong,Dan Zhao,Haihua Xiao,Bin Li

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Abstract

Overcoming the immunosuppressive tumor microenvironment and therapeutic resistance remains a significant challenge in ovarian cancer treatment. In this study, a glutathione-responsive polymeric nanoparticle platform for the co-delivery of the USP1 inhibitor SJB3-019A and the PARP inhibitor Niraparib is developed. This system synergistically enhances DNA damage accumulation, suppresses homologous recombination repair, and robustly activate the STING signaling pathway, leading to enhanced type I interferon responses and mitigation of immune evasion. Mechanistically, USP1 inhibition significantly impairs DNA repair, amplifying the synthetic lethality of PARP inhibition and promoting immunogenic cell death. In vivo studies demonstrated precise, glutathione-responsive drug release and substantial tumor accumulation of the nanoparticles, resulting in remarkable antitumor efficacy in murine ovarian cancer models. Importantly, this combinational approach effectively remodels the tumor microenvironment by increasing CD8⁺ T cell infiltration and enhancing tumor sensitivity to immune checkpoint blockade therapies. This innovative strategy targeting DNA damage responses presents a promising platform for precise and effective ovarian cancer immunotherapy.

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聚合物- parpi缀合物递送USP1i以最大限度地刺激高级别浆液性卵巢癌的STING通路

克服免疫抑制肿瘤微环境和治疗耐药性仍然是卵巢癌治疗的重大挑战。在这项研究中，开发了谷胱甘肽响应的聚合物纳米颗粒平台，用于共同递送USP1抑制剂SJB3-019A和PARP抑制剂Niraparib。该系统协同增强DNA损伤积累，抑制同源重组修复，稳健激活STING信号通路，从而增强I型干扰素应答，减轻免疫逃避。在机制上，USP1抑制显著损害DNA修复，放大PARP抑制的合成致命性，促进免疫原性细胞死亡。体内研究表明，精确的谷胱甘肽反应性药物释放和大量的纳米颗粒肿瘤积聚，在小鼠卵巢癌模型中产生显着的抗肿瘤功效。重要的是，这种组合方法通过增加CD8 + T细胞浸润和增强肿瘤对免疫检查点阻断疗法的敏感性，有效地重塑了肿瘤微环境。这种针对DNA损伤反应的创新策略为精确有效的卵巢癌免疫治疗提供了一个有希望的平台。

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来源期刊

Advanced Materials 工程技术-材料科学：综合

CiteScore

43.00

自引率

4.10%

发文量

2182

审稿时长

2 months

期刊介绍： Advanced Materials, one of the world's most prestigious journals and the foundation of the Advanced portfolio, is the home of choice for best-in-class materials science for more than 30 years. Following this fast-growing and interdisciplinary field, we are considering and publishing the most important discoveries on any and all materials from materials scientists, chemists, physicists, engineers as well as health and life scientists and bringing you the latest results and trends in modern materials-related research every week.