pH-responsive tannic acid-iron nanozymes capable of self-adaptive regulation of oxidative stress for enhancing the treatment of MRSA-infected wound via disrupting PBP2a to restore methicillin sensitivity

The treatment of bacterial wound infection, particularly that caused by methicillin-resistant Staphylococcus aureus (MRSA), presents significant challenges owing to biofilm formation, multidrug resistance, and immune evasion. Here, we have rationally designed a multifunctional composite nanozyme (FTM) consisting of tannic acid (TA) and ferric ion (Fe 3+ ) coordination compound loaded with antibiotic drug methicillin (Meth), which is capable of realizing pH-responsive self-adaptive regulation of oxidative stress for enhancing the treatment of MRSA-infected wound. During the early stages of wound infection (pH < 6.5), FTM demonstrates significant peroxidase-like activity for effectively catalyzing the conversion of endogenous H 2 O 2 into highly toxic hydroxyl radical (•OH), which not only directly damages MRSA and eliminates its biofilm for chemodynamic therapy (CDT), but also disrupts the penicillin-binding protein 2a (PBP2a) to restore the sensitivity of MRSA to methicillin. Meanwhile, FTM exhibits strong near-infrared (NIR) absorption, achieving photothermal antibacterial therapy (PTT). While in the later stages (after complete elimination of MRSA), as the infectious microenvironment of wound becomes neutral (pH 7.4), FTM mainly reveals the superoxide dismutase (SOD)-like activity for scavenging excess reactive oxygen species (ROS), ultimately reducing oxidative stress and promoting tissue repair. In vitro and in vivo experiments show that the proposed FTM nanozyme with triple bactericidal modalities achieves satisfactory antibacterial and antibiofilm therapy and accelerates wound healing process. Consequently, by adapting to the dynamic changes of wound microenvironment, this multifunctional nanoplatform offers a promising strategy for treating drug-resistant wound infections.