Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
ACS Appl Mater Interfaces. 2022 Mar 2;14(8):10117-10124. doi: 10.1021/acsami.1c23213. Epub 2022 Feb 18.
Bioorthogonal catalysis provides a powerful tool to perform non-natural chemical reactions in living systems to dissect complex intracellular processes. Its potency to precisely regulate cellular function, however, is limited by the lack of bioorthogonal catalysts with cell selectivity. Herein, we report that palladium nanoparticles deposited on metal-organic frameworks, Pd@UiO-66, are highly efficient for intracellular bioorthogonal catalysis. In addition, introducing a cancer cell-targeting aptamer, AS1411, onto Pd@UiO-66 enables a threefold enhancement of catalysis efficiency in cancer cells. Moreover, AS1411@Pd@UiO-66 is effective in activating chemically caged 4-hydroxytamoxifen to regulate the activity of a protein destabilizing domain, ER50, and therefore protein function selectively in cancer cells. We show that the control over the activity of a bacterial effector, OspF, using AS1411@Pd@UiO-66 inactivates mitogen-activated protein kinase (MAPK) signaling of cancer cells to selectively prohibit tumor cell growth. We believe that the strategy developed herein for cell-selective bioorthogonal catalysis can expand the chemical biology toolbox for spatiotemporal control of protein function for advanced therapeutic applications.
生物正交催化为在活系统中进行非天然化学反应提供了一种强大的工具，可用于剖析复杂的细胞内过程。然而，其精确调节细胞功能的效力受到缺乏具有细胞选择性的生物正交催化剂的限制。在此，我们报告负载在金属有机骨架（Pd@UiO-66）上的钯纳米粒子在细胞内生物正交催化中具有很高的效率。此外，将癌细胞靶向适体 AS1411 引入到 Pd@UiO-66 上，可使癌细胞中的催化效率提高三倍。此外，AS1411@Pd@UiO-66 可有效激活化学笼状 4-羟基他莫昔芬，以调节蛋白不稳定结构域 ER50 的活性，从而选择性地调节癌细胞中的蛋白功能。我们表明，使用 AS1411@Pd@UiO-66 控制细菌效应物 OspF 的活性可使 MAPK 信号失活，从而选择性地阻止肿瘤细胞生长。我们相信，本文开发的用于细胞选择性生物正交催化的策略可以扩展化学生物学工具包，用于蛋白质功能的时空控制，以实现先进的治疗应用。
