Wang Shuyu, Cheng Miaomiao, Wang Shenghui, Jiang Wei, Yang Feifei, Shen Xiaomei, Zhang Lirong, Yan Xiyun, Jiang Bing, Fan Kelong
Nanozyme Laboratory in Zhongyuan, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, China.
Adv Mater. 2024 Sep;36(39):e2403921. doi: 10.1002/adma.202403921. Epub 2024 Aug 5.
Radiotherapy (RT), essential for treating various cancers, faces challenges from tumor hypoxia, which induces radioresistance. A tumor-targeted "prosthetic-Arginine" coassembled nanozyme system, engineered to catalytically generate nitric oxide (NO) and oxygen (O) in the tumor microenvironment (TME), overcoming hypoxia and enhancing radiosensitivity is presented. This system integrates the prosthetic heme of nitric oxide synthase (NOS) and catalase (CAT) with NO-donating Fmoc-protected Arginine and Ru ions, creating HRRu nanozymes that merge NOS and CAT functionalities. Surface modification with human heavy chain ferritin (HFn) improves the targeting ability of nanozymes (HRRu-HFn) to tumor tissues. In the TME, strategic arginine incorporation within the nanozyme allows autonomous O and NO release, triggered by endogenous hydrogen peroxide, elevating NO and O levels to normalize vasculature and improve blood perfusion, thus mitigating hypoxia. Employing the intrinsic O-transporting ability of heme, HRRu-HFn nanozymes also deliver O directly to the tumor site. Utilizing esophageal squamous cell carcinoma as a tumor model, the studies reveal that the synergistic functions of NO and O production, alongside targeted delivery, enable the HRRu-HFn nanozymes to combat tumor hypoxia and potentiate radiotherapy. This HRRu-HFn nanozyme based approach holds the potential to reduce the radiation dose required and minimize side effects associated with conventional radiotherapy.
放射疗法（RT）是治疗各种癌症的关键，但面临肿瘤缺氧导致的放射抗性挑战。本文提出了一种肿瘤靶向的“人工精氨酸”共组装纳米酶系统，该系统经设计可在肿瘤微环境（TME）中催化生成一氧化氮（NO）和氧气（O），从而克服缺氧并增强放射敏感性。该系统将一氧化氮合酶（NOS）和过氧化氢酶（CAT）的人工血红素与供NO的Fmoc保护精氨酸和Ru离子整合在一起，创建了兼具NOS和CAT功能的HRRu纳米酶。用人重链铁蛋白（HFn）进行表面修饰可提高纳米酶（HRRu-HFn）对肿瘤组织的靶向能力。在TME中，纳米酶中精氨酸的巧妙掺入可实现由内源性过氧化氢触发的自主O和NO释放，提高NO和O水平以使血管系统正常化并改善血液灌注，从而缓解缺氧。利用血红素固有的O转运能力，HRRu-HFn纳米酶还可将O直接输送到肿瘤部位。以食管鳞状细胞癌为肿瘤模型的研究表明，NO和O生成的协同功能以及靶向递送使HRRu-HFn纳米酶能够对抗肿瘤缺氧并增强放射治疗效果。这种基于HRRu-HFn纳米酶的方法有可能降低所需的辐射剂量，并使与传统放疗相关的副作用最小化。
