Nitrogen-Centered Lactate Oxidase Nanozyme for Tumor Lactate Modulation and Microenvironment Remodeling

Designing nanozymes that match natural enzymes have always been an attractive and challenging goal. In general, researchers mainly focus on the construction of metal centers and the control of non-metallic ligands of nanozyme to regulate their activities. However, this is not applicable to lactate oxidase, i.e., flavoenzymes with flavin mononucleotide (FMN)-dependent pathways. Herein, we propose a coordination strategy to mimic lactate oxidase based on engineering the electronic properties at the N center by modulating the Co number near N in the Co_x–N nanocomposite. Benefitting from the manipulated coordination fields and electronic structure around the electron-rich N sites, Co₄N/C possesses a precise recognition site for lactate and intermediate organization and optimizes the absorption energies for intermediates, leading to superior oxidation of the lactate α-C–sp(3)–H bond toward ketone. The optimized nanozyme delivers much improved anticancer efficacy by reversing the high lactate and the immunosuppressive state of the tumor microenvironment, subsequently achieving excellent tumor growth and distant metastasis inhibition. The developed Co₄N/C NEs open a new window for building a bridge between chemical catalysis and biocatalysis.