A Cross‐Kingdom Counter‐Mimicry Nanozyme Reverses Fungal‐Induced Neutrophil Paralysis and Establishes Protective Immune Memory

ABSTRACT Recurrent fungal infections caused by Candida albicans remain a formidable clinical challenge due to the pathogen's sophisticated orchestration of immune evasion. Herein, we report a “kill‐and‐reset” nano‐platform comprising a CuFe dual‐atom nanozyme core encapsulated within a PD‐L1‐mimicking molecularly imprinted polymer shell (CuFe DAs‐MIP). This platform reverses pathogen‐induced immune paralysis and establishes long‐term protective memory. By leveraging the sequence and structural mimicry between the PD‐L1 epitope and Als3, the MIP shell acts as a competitive decoy to intercept this cross‐kingdom signaling axis, interrupting the JAK2/STAT3 signaling cascade, thereby restoring neutrophil chemokine (CXCL1/CXCL2) expression and recruitment. Simultaneously, the CuFe dual‐atom core exhibits adaptive catalytic switching. It generates a lethal reactive oxygen species burst within acidic biofilms, while at physiological pH it transitions to an antioxidative mode that promotes a 21.3‐fold increase in angiogenesis. In infectious wound models, this synergistic intervention achieves a 96.7% reduction in total fungal burden and significantly accelerates healing. Beyond localized therapy, the platform facilitates systemic immune education, expanding splenic memory B cells by 2.8‐fold to provide complete protection against secondary challenges. By bridging precision material chemistry with immunomodulation, this counter‐mimicry strategy offers a versatile paradigm for treating immune‐evasive infections and preventing their recurrence.