Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, Jilin, P. R. China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, P. R. China.
J Am Chem Soc. 2024 Mar 27;146(12):8216-8227. doi: 10.1021/jacs.3c12726. Epub 2024 Mar 14.
Bioorthogonal reactions provide a powerful tool to manipulate biological processes in their native environment. However, the transition-metal catalysts (TMCs) for bioorthogonal catalysis are limited to low atomic utilization and moderate catalytic efficiency, resulting in unsatisfactory performance in a complex physiological environment. Herein, sulfur-doped Fe single-atom catalysts with atomically dispersed and uniform active sites are fabricated to serve as potent bioorthogonal catalysts (denoted as Fe-SA), which provide a powerful tool for in situ manipulation of cellular biological processes. As a proof of concept, the N-methyladensoine (mA) methylation in macrophages is selectively regulated by the mannose-modified Fe-SA nanocatalysts (denoted as Fe-SA@Man NCs) for potent cancer immunotherapy. Particularly, the agonist prodrug of mA writer METTL3/14 complex protein (pro-MPCH) can be activated in situ by tumor-associated macrophage (TAM)-targeting Fe-SA@Man, which can upregulate METTL3/14 complex protein expression and then reprogram TAMs for tumor killing by hypermethylation of mA modification. Additionally, we find the NCs exhibit an oxidase (OXD)-like activity that further boosts the upregulation of mA methylation and the polarization of macrophages via producing reactive oxygen species (ROS). Ultimately, the reprogrammed M1 macrophages can elicit immune responses and inhibit tumor proliferation. Our study not only sheds light on the design of single-atom catalysts for potent bioorthogonal catalysis but also provides new insights into the spatiotemporal modulation of mA RNA methylation for the treatment of various diseases.
生物正交反应为在其天然环境中操作生物过程提供了一种强大的工具。然而，用于生物正交催化的过渡金属催化剂（TMCs）仅限于低原子利用率和中等催化效率，导致在复杂的生理环境中的性能不理想。在此，制备了具有原子分散和均匀活性位的硫掺杂 Fe 单原子催化剂作为有效的生物正交催化剂（表示为 Fe-SA），为原位操作细胞生物过程提供了有力的工具。作为概念验证，通过甘露糖修饰的 Fe-SA 纳米催化剂（表示为 Fe-SA@Man NCs）选择性调节巨噬细胞中的 N-甲基腺苷（mA）甲基化，用于有效的癌症免疫治疗。特别是，mA 写入器 METTL3/14 复合物蛋白的激动剂前药（pro-MPCH）可以通过肿瘤相关巨噬细胞（TAM）靶向的 Fe-SA@Man 原位激活，从而上调 METTL3/14 复合物蛋白的表达，然后通过 mA 修饰的超甲基化重新编程 TAMs 以杀死肿瘤。此外，我们发现 NCs 表现出氧化酶（OXD）样活性，通过产生活性氧（ROS）进一步促进 mA 甲基化的上调和巨噬细胞的极化。最终，重编程的 M1 巨噬细胞可以引发免疫反应并抑制肿瘤增殖。我们的研究不仅为高效生物正交催化的单原子催化剂设计提供了思路，也为 mA RNA 甲基化的时空调节提供了新的见解，可用于治疗各种疾病。
