Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, 100190, Beijing, China.
University of Chinese Academy of Sciences, 100049, Beijing, China.
Angew Chem Int Ed Engl. 2023 Nov 27;62(48):e202312784. doi: 10.1002/anie.202312784. Epub 2023 Oct 23.
Mitochondria-targeted bioorthogonal catalysis holds promise for controlling cell function precisely, yet achieving selective and efficient chemical reactions within organelles is challenging. In this study, we introduce a new strategy using protein-integrated hydrogen-bonded organic frameworks (HOFs) to enable synergistic bioorthogonal chemical catalysis and enzymatic catalysis within mitochondria. Utilizing catalytically active tris(4,4'-dicarboxylicacid-2,2'-bipyridyl) ruthenium(II) to self-assemble with [1,1'-biphenyl]-4,4'-biscarboximidamide, we synthesized nanoscale RuB-HOFs that exhibit high photocatalytic reduction activity. Notably, RuB-HOFs efficiently enter cells and preferentially localize to mitochondria, where they facilitate bioorthogonal photoreduction reactions. Moreover, we show that RuB-HOFs encapsulating catalase can produce hydrogen sulfide (H S) in mitochondria through photocatalytic reduction of pro-H S and degrade hydrogen peroxide through enzymatic catalysis simultaneously, offering a significant neuroprotective effect against oxidative stress. Our findings not only introduce a versatile chemical toolset for mitochondria-targeted bioorthogonal catalysis for prodrug activation but also pave the way for potential therapeutic applications in treating diseases related to cellular oxidative stress.
线粒体靶向生物正交催化有望精确控制细胞功能，但实现在细胞器内进行选择性和高效的化学反应具有挑战性。在这项研究中，我们引入了一种新策略，使用整合蛋白的氢键有机框架（HOFs），在线粒体中实现协同生物正交化学催化和酶催化。利用催化活性的三（4,4'-二羧酸-2,2'-联吡啶）钌（II）与[1,1'-联苯]-4,4'-双脒自组装，我们合成了表现出高光催化还原活性的纳米级 RuB-HOFs。值得注意的是，RuB-HOFs 能够有效地进入细胞，并优先定位于线粒体，在那里它们促进生物正交光还原反应。此外，我们表明，包封过氧化氢酶的 RuB-HOFs 可以通过前体 H S 的光催化还原在线粒体中产生硫化氢（H S），并通过酶催化同时降解过氧化物，提供针对氧化应激的显著神经保护作用。我们的发现不仅为用于前药激活的线粒体靶向生物正交催化引入了多功能化学工具包，而且为治疗与细胞氧化应激相关的疾病的潜在治疗应用铺平了道路。
