Manipulating Radiation‐Sensitive Z‐DNA Conformation for Enhanced Radiotherapy
Dongmei Wang, You Liao, Hao Zeng, Chenglu Gu, Xue Wang, Shuang Zhu, Xihong Guo, Jie Zhang, Ziye Zheng, Junfang Yan, Fuquan Zhang, Lingmi Hou, Zhanjun Gu, Baoyun Sun
Abstract
Abstract 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 2 nanocapsules loaded with a Z‐DNA inducer CBL0137, is proposed. A hollow mesoporous HfO 2 (HM‐HfO 2 ) 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 2 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.