概述放射癌症疗法使用不同的电离辐射质量，通过尚未完全了解的大量机制和过程来损害肿瘤细胞中的 DNA 分子。虽然辐射的直接作用很重要，但水辐射分解的副产物，主要是二次低能电子（LEE，<20 eV）和活性氧（ROS），也可以有效地导致 DNA 损伤（就 DNA 链而言）断裂或 DNA 链间交联。结果，这些类型的 DNA 损伤演变成阻碍 DNA 复制的突变，导致癌细胞死亡。同步放化疗探索添加通常针对 DNA 的放射增敏疗法，例如铂衍生物和卤化核苷，以增强电离辐射对 DNA 分子的有害影响。端粒 DNA 中出现的 G-四链体等二级结构使 DNA 损伤的情况进一步复杂化。这些结构可以保护 DNA 免受辐射损伤，使它们成为新的、更具选择性的癌症放射治疗的有希望的目标，而不是针对线性 DNA。然而，尽管进行了广泛的研究，仍然没有单一的范式方法来理解电离辐射导致 DNA 损伤的神秘方式。这是由于该研究领域的多学科性质，涉及生物组织的多个层次，从生命的分子构建模块到细胞和生物体，以及复杂的多尺度辐射引起的效应。此外，DNA 的内在特征，例如 DNA 拓扑结构和特定的寡核苷酸序列，也会强烈影响其对电离辐射损伤的反应。在本报告中，我们介绍的研究重点是战略性选择的目标 DNA 序列中光子和低能电子诱导的 DNA 损伤的绝对定量。我们的方法涉及使用 DNA 折纸纳米结构，特别是 Rothemund 三角，作为将 DNA 序列暴露于低能电子或真空紫外线 (VUV，<15 eV) 光子的平台，并随后进行原子力显微镜 (AFM) 分析。通过这种方法，DNA 序列、卤化放射增敏剂的掺入、DNA 拓扑结构和辐射质量对辐射引起的 DNA 链断裂的影响已得到系统评估，并与 DNA 辐射损伤背后的基本光子和电子驱动机制相关联。在较低能量下，这些机制包括解离电子附着 (DEA)（电子附着到 DNA 分子上导致链断裂）和 DNA 解离光激发。此外，进一步的解离过程（例如光电离和电子碰撞）会导致电离辐射引起的 DNA 损伤事件的复杂级联。我们预计新兴的基于 DNA 折纸的方法将导致与 DNA 损伤相关的研究领域发生范式转变，并提出未来的方向，这可以促进纳米医学技术应用的发展，例如优化的癌症治疗或优化放射增敏的分子设计疗法。

ConspectusRadiation cancer therapies use different ionizing radiation qualities that damage DNA molecules in tumor cells by a yet not completely understood plethora of mechanisms and processes. While the direct action of the radiation is significant, the byproducts of the water radiolysis, mainly secondary low-energy electrons (LEEs, <20 eV) and reactive oxygen species (ROS), can also efficiently cause DNA damage, in terms of DNA strand breakage or DNA interstrand cross-linking. As a result, these types of DNA damage evolve into mutations hindering DNA replication, leading to cancer cell death. Concomitant chemo-radiotherapy explores the addition of radiosensitizing therapeutics commonly targeting DNA, such as platinum derivatives and halogenated nucleosides, to enhance the harmful effects of ionizing radiation on the DNA molecule. Further complicating the landscape of DNA damage are secondary structures such as G-quadruplexes occurring in telomeric DNA. These structures protect DNA from radiation damage, rendering them as promising targets for new and more selective cancer radiation treatments, rather than targeting linear DNA. However, despite extensive research, there is no single paradigm approach to understanding the mysterious way in which ionizing radiation causes DNA damage. This is due to the multidisciplinary nature of the field of research, which deals with multiple levels of biological organization, from the molecular building blocks of life toward cells and organisms, as well as with complex multiscale radiation-induced effects. Also, intrinsic DNA features, such as DNA topology and specific oligonucleotide sequences, strongly influence its response to damage from ionizing radiation. In this Account, we present our studies focused on the absolute quantification of photon- and low-energy electron-induced DNA damage in strategically selected target DNA sequences. Our methodology involves using DNA origami nanostructures, specifically the Rothemund triangle, as a platform to expose DNA sequences to either low-energy electrons or vacuum-ultraviolet (VUV, <15 eV) photons and subsequent atomic force microscopy (AFM) analysis. Through this approach, the effects of the DNA sequence, incorporation of halogenated radiosensitizers, DNA topology, and the radiation quality on radiation-induced DNA strand breakage have been systematically assessed and correlated with fundamental photon- and electron-driven mechanisms underlying DNA radiation damage. At lower energies, these mechanisms include dissociative electron attachment (DEA), where electrons attach to DNA molecules causing strand breaks, and dissociative photoexcitation of DNA. Additionally, further dissociative processes such as photoionization and electron impact contribute to the complex cascade of DNA damage events induced by ionizing radiation. We expect that emerging DNA origami-based approaches will lead to a paradigm shift in research fields associated with DNA damage and suggest future directions, which can foster the development of technological applications in nanomedicine, e.g., optimized cancer treatments or the molecular design of optimized radiosensitizing therapeutics.