Bioinspired Design of Single-Atom Micellar Nanozymes Facilitates Internal Environment-Driven Synergistic Therapy against Lymphoma

The binding and catalytic sites of natural enzymes play a decisive role in enzymatic processes. Constructing bioinspired catalytic centers and advancing nanozyme-mediated cancer therapeutics represent a significant yet challenging frontier. Herein, we have developed tumor-targeting micellar single-atom nanozymes (Fe(II)NC-SAz-E5 micelles) through a rational design that integrates tumor microenvironment (TME) responsivity and active targeting for synergistic anti-Non-Hodgkin’s lymphoma (NHL) therapy. The Fe(II) ions were precisely anchored into PLGA-PEG-NH2 self-assembled micelle-DOTA-E5 complex via DOTA chelation, forming FeN4(COOH) active sites that mimic natural peroxidase with remarkable catalytic efficiency. Guided by the tumor-targeting peptide E5, these micelles preferentially accumulate in tumor tissues and inhibit metastasis by suppressing the CXCR4/CXCL12 signaling axis. Moreover, tumor cells are effectively eliminated through a self-sustaining cycle of “substrate supply-catalytic amplification-metabolic intervention,” leveraging the elevated levels of H2O2, GSH, and glucose in the TME. Extensive in vitro and in vivo studies demonstrated the micelles’ potent catalytic activity, significant inhibition of lymphoma progression, and strong antimetastatic effects. Notably, the use of FDA-approved PLGA and clinically established DOTA chelation highlights the strong translational potential of this platform for future clinical applications.