Phage‐Derived Protein‐Guided Nanozymes for the Treatment of MRSA‐Infected Acute Otitis Media

ABSTRACT Nanozymes with peroxidase‐like activity have been identified as promising nanomaterials against antimicrobial resistance. However, their in vivo efficacy is significantly limited due to the lack of bacterial targeting ability. Furthermore, the substantial accumulation of nanozymes in nontarget tissues raises concerns of potential nanotoxicity. Here, we report a single‐atom nanozyme (mFeP‑gCBD) by coupling ferriporphyrin containing monocarboxyphenyl (mFeP) and cell wall binding domain of endolysin from Staphylococcus aureus phage via a bioorthogonal reaction to achieve targeted catalytic elimination of methicillin‐resistant Staphylococcus aureus (MRSA). This nanoplatform can actively recognize MRSA in the infection microenvironment and generate high intensity of reactive oxygen species through its intrinsic peroxidase‐like activity, ultimately destroying the structure and biofilm of MRSA. Experimental results demonstrate that mFeP‑gCBD displays 20 times reduction in the effective antibacterial dose compared to untargeted mFeP. In an acute otitis media model infected with MRSA, 2 µg mL – 1 of mFeP‑gCBD significantly alleviates inflammation in the middle ear cavity and recovers mouse auditory thresholds. Remarkably, such a low applied dosage avoids dysbiosis of the commensal bacteria community and systemic toxicity. This work provides a modular design strategy for nanozymes with bacterial targeting capacity.