Wang Dongmei, Liao You, Zeng Hao, Gu Chenglu, Wang Xue, Zhu Shuang, Guo Xihong, Zhang Jie, Zheng Ziye, Yan Junfang, Zhang Fuquan, Hou Lingmi, Gu Zhanjun, Sun Baoyun
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China.
College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China.
Adv Mater. 2024 Jul;36(29):e2313991. doi: 10.1002/adma.202313991. Epub 2024 May 9.
DNA double-strand breaks (DSBs) yield highly determines radiotherapy efficacy. However, improving the inherent radiosensitivity of tumor DNA to promote radiation-induced DSBs remains a challenge. Using theoretical and experimental models, the underexplored impact of Z-DNA conformations on radiosensitivity, yielding higher DSBs than other DNA conformations, is discovered. Thereout, a radiosensitization strategy focused on inducing Z-DNA conformation, utilizing CBL@HfO nanocapsules loaded with a Z-DNA inducer CBL0137, is proposed. A hollow mesoporous HfO (HM-HfO) acts as a delivery and an energy depositor to promote Z-DNA breakage. The nanocapsule permits the smart DSBs accelerator that triggers its radiosensitization with irradiation stimulation. Impressively, the CBL@HfO facilitates the B-Z DNA conformational transition, augmenting DSBs about threefold stronger than irradiation alone, generating significant tumor suppression with a 30% cure rate. The approach enables DSBs augmentation by improving the inherent radiosensitivity of DNA. As such, it opens up an era of Z-DNA conformation manipulation in radiotherapy.
DNA双链断裂（DSB）的产生高度决定放疗疗效。然而，提高肿瘤DNA的固有放射敏感性以促进辐射诱导的DSB仍然是一项挑战。通过理论和实验模型，发现了Z-DNA构象对放射敏感性的影响尚未得到充分研究，其产生的DSB比其他DNA构象更多。由此，提出了一种聚焦于诱导Z-DNA构象的放射增敏策略，利用负载Z-DNA诱导剂CBL0137的CBL@HfO纳米胶囊。中空介孔HfO（HM-HfO）作为递送载体和能量沉积剂来促进Z-DNA断裂。该纳米胶囊允许智能DSB加速器通过辐射刺激触发其放射增敏作用。令人印象深刻的是，CBL@HfO促进B-Z DNA构象转变，增强的DSB比单独照射强约三倍，产生显著的肿瘤抑制效果，治愈率达30%。该方法通过提高DNA的固有放射敏感性来增强DSB。因此，它开启了放疗中Z-DNA构象操纵的时代。
