Manipulating Radiation-Sensitive Z-DNA Conformation for Enhanced Radiotherapy.

DNA double-strand breaks (DSBs) yield highly determines radiotherapy efficacy. However, improving the inherent radiosensitivity of tumour DNA to promote radiation-induced DSBs remains a challenge. Using theoretical and experimental models, we discover the underexplored impact of Z-DNA conformations on radiosensitivity, yielding higher DSBs than other DNA conformations. Thereout, we propose a radiosensitization strategy focused on inducing Z-DNA conformation, utilizing CBL@HfO 2 nanocapsules loaded with a Z-DNA inducer CBL0137. 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 4-fold stronger than irradiation alone, generating significant tumour 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. This article is protected by copyright. All rights reserved.