Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, School of Biomedical Engineering, National Center for Translational Medicine, Zhang Jiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, 200240, China.
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Adv Mater. 2024 Nov;36(45):e2410031. doi: 10.1002/adma.202410031. Epub 2024 Sep 9.
During fractionated radiotherapy, DNA damage repair intensifies in tumor cells, culminating in cancer radioresistance and subsequent radiotherapy failure. Despite the recent development of nanoradiosensitizers targeting specific DNA damage repair pathways, the persistence of repair mechanisms involving multiple pathways remains inevitable. To address this challenge, a nucleophilicity-engineered DNA ligation blockade nanoradiosensitizer (DLBN) comprising Au/CeO heteronanostructure modified with trans-acting activator of transcription peptides is reported, which targets and inhibits the DNA ligation inside cancer cell nuclei via heterointerface-mediated dephosphorylation of DNA, a crucial step in overcoming cancer radioresistance. First, the Schottky-type heteronanostructure of cancer cell nucleus-targeting DLBN effectively intensifies radiation-induced DNA damage via catalase-mimetic activity and radiation-triggered catalytic reactions. Notably, by leveraging Au/CeO heterointerface, DLBN spontaneously dissociates HO to hydroxide, a nucleophile with higher nucleophilicity, thereby exhibiting remarkable dephosphorylation capability at DNA nicks through facilitated nucleophilic attack. This enables the blockade of DNA ligation, a pivotal step in all DNA damage repair pathways, effectively interrupting the repair process. Consequently, DLBN resensitizes radioresistant cells by overcoming therapy-induced radioresistance, leading to a substantial accumulation of unrepaired DNA damage. These findings offer insight into the dephosphorylation of DNA within nuclei, and underscore the potential of heteronanostructure-based nanoradiosensitizer to block DNA ligation against therapy-induced radioresistance.
在分次放射治疗中，肿瘤细胞内的 DNA 损伤修复会加剧，最终导致癌症放射抵抗和随后的放射治疗失败。尽管最近针对特定 DNA 损伤修复途径的纳米增敏剂有所发展，但涉及多个途径的修复机制的持续存在仍然不可避免。为了解决这一挑战，报告了一种包含 Au/CeO 杂化纳米结构的亲核性 DNA 连接阻断纳米增敏剂（DLBN），该纳米结构经过转录激活因子转导肽修饰，可通过异质界面介导的 DNA 去磷酸化靶向并抑制癌细胞核内的 DNA 连接，这是克服癌症放射抵抗的关键步骤。首先，具有癌细胞核靶向功能的 DLBN 的肖特基型杂化纳米结构通过类过氧化物酶活性和辐射触发的催化反应有效地增强了辐射诱导的 DNA 损伤。值得注意的是，利用 Au/CeO 异质界面，DLBN 自发地将 HO 解离为氢氧根，一种亲核性更高的亲核试剂，从而通过促进亲核攻击在 DNA 切口处表现出显著的去磷酸化能力。这使得 DNA 连接的阻断成为可能，这是所有 DNA 损伤修复途径中的关键步骤，有效地中断了修复过程。因此，DLBN 通过克服治疗诱导的放射抵抗使耐辐射细胞重新敏感，导致未修复的 DNA 损伤大量积累。这些发现提供了对细胞核内 DNA 去磷酸化的深入了解，并强调了基于杂化纳米结构的纳米增敏剂阻断 DNA 连接以对抗治疗诱导的放射抵抗的潜力。
