Lysostaphin bioengineered cascade nanoreactor for bacterial eradication and inflammatory remodeling in MRSA pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a life-threatening infectious disease, yet current antibiotic-centered therapies remain insufficient to achieve satisfactory therapeutic outcomes. Herein, a lysostaphin-bioengineered cascade nanoreactor, LO-PDA/Zn@CA, is developed for the integrated treatment of MRSA pneumonia. This system consists of cinnamaldehyde (CA)-loaded, Zn2+-chelated polydopamine nanoparticles coated with lysostaphin-engineered bacterial outer membrane vesicles. Upon reaching MRSA-infected lung lesions, CA disrupts the biofilm matrix and compromises bacterial membranes, thereby weakening extracellular protective barriers. Zn2+ subsequently activates surface-displayed lysostaphin to specifically hydrolyze pentaglycine cross-bridges within the MRSA peptidoglycan cell wall, further breaching bacterial integrity and promoting intrabacterial penetration of CA and Zn2+. The released Zn2+ induces lethal DNA damage-associated responses, collectively amplifying bactericidal efficacy through a stepwise antibacterial cascade. In parallel, the PDA/Zn nanocore scavenges excessive reactive oxygen species, suppresses glycolytic reprogramming, and downregulates H3K27ac-dependent transcription of pro-inflammatory genes, thereby attenuating macrophage M1 polarization and mitigating pulmonary inflammatory injury. In vitro and in vivo studies demonstrate that LO-PDA/Zn@CA effectively eliminates planktonic MRSA, disrupts established biofilms, and alleviates MRSA-induced pulmonary inflammation with favorable biosafety. By integrating pathogen-specific bacterial eradication with inflammation resolution in a cascade manner, this work provides a versatile nanotherapeutic strategy for the treatment of drug-resistant MRSA pneumonia.