Li Hui, Zeng Junyi, You Qing, Zhang Miaomiao, Shi Yuanchao, Yang Xiaodong, Gu Wenxing, Liu Yajie, Hu Ning, Wang Yu, Chen Xiaoyuan, Mu Jing
Institute of Precision Medicine, Peking University Shenzhen Hospital, 518036, Shenzhen, China; Departments of Diagnostic Radiology, Surgery, 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.
Institute of Precision Medicine, Peking University Shenzhen Hospital, 518036, Shenzhen, China; Key Laboratory of Biorheological Science and Technology, Ministry of Education and Bioengineering College, Chongqing University, Chongqing, 400044, China.
Biomaterials. 2025 May;316:123031. doi: 10.1016/j.biomaterials.2024.123031. Epub 2024 Dec 16.
Radiotherapy, employing high-energy rays to precisely target and eradicate tumor cells, plays a pivotal role in the treatment of various malignancies. Despite its therapeutic potential, the effectiveness of radiotherapy is hindered by the tumor's inherent low radiosensitivity and the immunosuppressive microenvironment. Here we present an innovative approach that integrates peroxynitrite (ONOO)-mediated radiosensitization with the tumor-associated neutrophils (TANs) polarization for the reversal of immunosuppressive tumor microenvironment (TME), greatly amplifying the potency of radiotherapy. Our design employs X-ray-activated lanthanide-doped scintillators (LNS) in tandem with photosensitive NO precursor to achieve in-situ ONOO generation. Concurrently, the co-loaded TGF-β inhibitor SB525334, released from the LNS-RS nanoplatform in response to the overexpressed GSH in tumor site, promotes the reprogramming of TANs from N2 phenotype toward N1 phenotype, effectively transforming the tumor-promoting microenvironment into a tumor-inhibiting state. This 'one-two punch' therapy efficiently trigger a robust anti-tumor immune response and exert potent therapeutic effects in orthotopic colorectal cancer and melanoma mouse model. Meanwhile, it also significantly prevents liver metastasis and recurrence in metastatic colorectal cancer. The development of X-ray-controlled platforms capable of activating multiple therapeutic modalities may accelerate the clinical application of radiotherapy-based collaborative therapy.
放射疗法利用高能射线精确靶向并消灭肿瘤细胞，在各种恶性肿瘤的治疗中发挥着关键作用。尽管具有治疗潜力，但肿瘤固有的低放射敏感性和免疫抑制微环境阻碍了放射疗法的有效性。在此，我们提出一种创新方法，将过氧亚硝酸盐（ONOO）介导的放射增敏与肿瘤相关中性粒细胞（TANs）极化相结合，以逆转免疫抑制性肿瘤微环境（TME），极大地增强放射疗法的效力。我们的设计采用X射线激活的镧系掺杂闪烁体（LNS）与光敏NO前体串联，以实现原位生成ONOO。同时，负载的TGF-β抑制剂SB525334响应肿瘤部位过表达的谷胱甘肽从LNS-RS纳米平台释放，促进TANs从N2表型重编程为N1表型，有效地将促肿瘤微环境转变为抑肿瘤状态。这种“双管齐下”的疗法在原位结直肠癌和黑色素瘤小鼠模型中有效地引发强大的抗肿瘤免疫反应并发挥强大的治疗效果。同时，它还显著预防转移性结直肠癌的肝转移和复发。能够激活多种治疗方式的X射线控制平台的开发可能会加速基于放射疗法的联合治疗的临床应用。
