none 10.1038/s41467-024-46528-w Springer Science and Business Media LLC Springer Science and Business Media LLC 297 158828983 97145 20240313010138192 10.1038 2024-04-23T18:43:17Z 2024-03-13T00:02:14Z 84 Nature Communications Nat Commun 2041-1723 12 2024 15 1 Ying Wang http://orcid.org/0000-0003-3212-9653 Vinod K. Paidi http://orcid.org/0000-0002-1085-4988 Weizhen Wang http://orcid.org/0009-0009-6655-1589 Yong Wang http://orcid.org/0000-0002-1292-0459 Guangri Jia http://orcid.org/0000-0002-5669-430X Tingyu Yan http://orcid.org/0009-0008-3564-5016 Xiaoqiang Cui http://orcid.org/0000-0002-5858-6257 Songhua Cai http://orcid.org/0000-0003-3839-2030 Jingxiang Zhao http://orcid.org/0000-0001-6023-8887 Kug-Seung Lee http://orcid.org/0000-0002-7570-8404 Lawrence Yoon Suk Lee http://orcid.org/0000-0002-6119-4780 Kwok-Yin Wong http://orcid.org/0000-0003-4984-7109 Abstract The precise design of single-atom nanozymes (SAzymes) and understanding of their biocatalytic mechanisms hold great promise for developing ideal bio-enzyme substitutes. While considerable efforts have been directed towards mimicking partial bio-inspired structures, the integration of heterogeneous SAzymes configurations and homogeneous enzyme-like mechanism remains an enormous challenge. Here, we show a spatial engineering strategy to fabricate dual-sites SAzymes with atomic Fe active center and adjacent Cu sites. Compared to planar Fe–Cu dual-atomic sites, vertically stacked Fe–Cu geometry in FePc@2D-Cu–N–C possesses highly optimized scaffolds, favorable substrate affinity, and fast electron transfer. These characteristics of FePc@2D-Cu–N–C SAzyme induces biomimetic O 2 activation through homogenous enzymatic pathway, resembling functional and mechanistic similarity to natural cytochrome c oxidase. Furthermore, it presents an appealing alternative of cytochrome P450 3A4 for drug metabolism and drug–drug interaction. These findings are expected to deepen the fundamental understanding of atomic-level design in next-generation bio-inspired nanozymes. 03 12 2024 2239 46528 1 10.1007/springer_crossmark_policy link.springer.com false 9 June 2023 29 February 2024 12 March 2024 The authors declare no competing interests. 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