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 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.