Manipulating Radiation‐Sensitive Z‐DNA Conformation for Enhanced Radiotherapy

Abstract

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@HfO2 nanocapsules loaded with a Z‐DNA inducer CBL0137. A hollow mesoporous HfO2 (HM‐HfO2) 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@HfO2 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