Reengineering Aligned D-Orbital Energy Levels in FeMn Dual-Atom Nanozyme Inhibits Pyroptosis for Effective Alleviation of Inflammatory Diseases.

Abstract

Pyroptosis inhibition via Fe single-atom nanozymes is promising for inflammation therapy, but the common Fe-N₄ configuration restricts oxygen intermediate desorption and lacks cooperative sites, thus limiting catalytic performance. To overcome this, we develop a FeMn dual-atom nanozyme supported on oxygen-nitrogen-doped bamboo-like carbon nanotubes (FeMn_DA/BCNT). Through the precise alignment of Fe and Mn 3dz² orbital energy levels by the electron-delocalized BCNT support in the FeMn-N/O active center, thereby lowering the dissociation energy barrier for ^*O₂ or ^*H₂O molecules, promoting O─O bond cleavage to bypass toxic ─OOH species, and thus accelerating the enzyme-like kinetics. Combined with a hierarchical porous bamboo-like structure of the BCNT that enhances high specific surface, atom exposure, and mass transfer, the FeMn_DA/BCNT nanozymes exhibit potent superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)-like activities. Further encapsulation with a macrophage membrane ([MM]FeMn_DA/BCNT) confers excellent biocompatibility and active targeting ability toward inflammatory sites. The resulting [MM]FeMn_DA/BCNT nanozymes target the inflammatory microenvironment, scavenges ROS, restores mitochondrial function, and suppresses NLRP3 inflammasome activation, thereby inhibiting pyroptosis. In vivo, [MM]FeMn_DA/BCNT nanozymes show good biocompatibility and efficacy in treating osteoarthritis, acute liver injury, and acute kidney injury. This work provides a novel strategy for inflammatory disease therapy using a biomimetic dual-atom nanozyme.