Hongli Yang, Peihua Lin, Bo Zhang, Fangyuan Li, Daishun Ling
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引用次数: 0
Abstract
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/CeO2 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/CeO2 heterointerface, DLBN spontaneously dissociates H2O 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.
在分次放疗过程中,肿瘤细胞的 DNA 损伤修复会加剧,最终导致癌症放射抗性和放疗失败。尽管最近开发出了针对特定 DNA 损伤修复途径的纳米放射增敏剂,但涉及多种途径的修复机制的持续存在仍然不可避免。为了应对这一挑战,本研究报道了一种亲核性工程DNA连接阻断纳米放射增敏剂(DLBN),它由Au/CeO2异质结构和反式转录激活肽修饰而成,通过异质界面介导的DNA去磷酸化作用靶向并抑制癌细胞核内的DNA连接,这是克服癌症放射抗性的关键步骤。首先,癌细胞核靶向 DLBN 的肖特基型异质结构通过催化酶模拟活性和辐射触发的催化反应,有效地加剧了辐射诱导的 DNA 损伤。值得注意的是,通过利用金/CeO2 异质界面,DLBN 可自发地将 H2O 分解为氢氧化物(一种亲核性更高的亲核体),从而通过促进亲核攻击在 DNA 缺口处表现出显著的去磷酸化能力。这使得 DNA 连接(所有 DNA 损伤修复途径中的关键步骤)被阻断,从而有效地中断了修复过程。因此,DLBN 通过克服治疗引起的放射抗性,使放射抗性细胞重新敏感,从而导致大量未修复 DNA 损伤的积累。这些发现深入揭示了 DNA 在细胞核内的去磷酸化过程,并强调了基于异质结构的纳米放射增敏剂阻断 DNA 连接以对抗治疗诱导的放射抗性的潜力。
期刊介绍:
Advanced Materials, one of the world's most prestigious journals and the foundation of the Advanced portfolio, is the home of choice for best-in-class materials science for more than 30 years. Following this fast-growing and interdisciplinary field, we are considering and publishing the most important discoveries on any and all materials from materials scientists, chemists, physicists, engineers as well as health and life scientists and bringing you the latest results and trends in modern materials-related research every week.