Despite the promise of activatable chemotherapy, the development of a spatiotemporally controllable strategy for prodrug activation in deep tissues remains challenging. Herein, a proof‐of‐concept is proposed for a gold nanocluster‐based strategy that utilizes X‐ray irradiation to trigger the liberation of platinum (Pt)‐based prodrug conjugates, thus enabling radiotherapy‐directed chemotherapy. Mechanistically, the irradiated activation of prodrugs is achieved through direct photoelectron transfer from the excited‐state gold nanoclusters to the Pt(IV) center, resulting in the release of cytotoxic Pt(II) agents. Compared to the traditional combination of chemotherapy and radiotherapy, this radiotherapy‐directed chemotherapy strategy offers superior antitumor efficacy and safety benefits through spatiotemporal synergy at the tumor site. Additionally, this strategy elicits robust immunogenic cell death and yields profound outcomes for combined immunotherapy of breast cancer. This versatile strategy is ushering in a new era of radiation‐mediated chemistry for controlled drug delivery and the precise regulation of biological processes.

中文翻译：

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金纳米团簇：用于 X 射线激活化疗的光电转换器


尽管可激活化疗有望实现，但开发深部组织中前药激活的时空可控策略仍然具有挑战性。在此，提出了基于金纳米簇的策略的概念验证，该策略利用 X 射线照射触发基于铂 (Pt) 的前药缀合物的释放，从而实现放射治疗导向的化疗。从机制上讲，前药的辐照激活是通过从激发态金纳米团簇到 Pt(IV) 中心的直接光电子转移来实现的，从而释放细胞毒性 Pt(II) 剂。与传统的化疗和放疗联合治疗相比，这种以放疗为导向的化疗策略通过肿瘤部位的时空协同作用提供了优越的抗肿瘤疗效和安全性。此外，该策略引发强烈的免疫原性细胞死亡，并对乳腺癌的联合免疫治疗产生深远的影响。这种多功能策略正在开创辐射介导化学的新时代，用于受控药物输送和生物过程的精确调节。