ROS responsive micelles coloaded with Linezolid and Honokiol for targeting and synergistic therapy of Methicillin-resistant Staphylococcus aureus pneumonia

The growing crisis of bacterial resistance has prompted the development of novel antibacterial therapeutic systems to combat Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This study reports a nano-micelle system (RMLH-Ms) for the co-delivery of the antibiotic Linezolid and the traditional Chinese medicine monomer Honokiol. Antibacterial peptide Magainin II (Mag II) was employed to endow the micelles with bacterial targeting ability, and thioketal bond modification was used to confer ROS-responsive properties. Linezolid and Honokiol were successfully encapsulated into micelles with entrapment efficiencies (EE%>95%.) A low critical micelle concentration (CMC) of 0.0138 mg/mL and sustained colloidal stability over 21 days were observed. Mag II‑modified RMLH‑Ms appeared to show improved bacterial targeting ability compared with unmodified micelles. The ZIP score for Linezolid and Honokiol combination was 7.61, exhibiting a synergistic antibacterial effect. Micelles incorporated with honokiol (LH-Ms) reduced the MIC of L-Ms from 4 μg/mL to 2 μg/mL. Furthermore, the incorporation of Honokiol also exhibited additional anti-inflammatory, macrophage polarization regulation immune microenvironment regulating activities in vitro. In vivo, The survival rates were 12.5%, 37.5%, 50%, 62.5%, and 75% for the model group, L-Ms, LH-Ms, MLH-Ms, and RMLH-Ms group, respectively. The survival rate of the RMLH-Ms group rose by 62.5% compared with the model group. RMLH-Ms induced mild decreases in lung bacterial burden, mitigated inflammatory responses and alleviated pathological lung damage, exhibiting favorable in vivo activity under experimental conditions.