Hybrid vesicle-camouflaged cascade nanoreactors enable dual-targeted ferroptotic killing of intracellular MRSA and immune remodeling in pneumonia

We engineer a hybrid bacterial vesicle nanoreactor for refractory MRSA pneumonia. • Hybrid membrane enables dual-targeting cascade and vaccine-like immune activation. • Cinnamaldehyde/ferrocene trigger ferroptosis to kill MRSA and disrupt biofilms. • Nanoreactor induces M2 polarization, reducing inflammation and boosting immunity. Intracellular methicillin-resistant Staphylococcus aureus MRSA pneumonia remains difficult to treat because bacteria can survive within macrophages, where poor antibiotic penetration, intracellular persistence, and dysregulated inflammation collectively drive recurrent infection. Here, we developed a hybrid bacterial vesicle-camouflaged cascade nanoreactor PCFP/CA@HMV for dual-targeted intracellular MRSA eradication and pulmonary immune remodeling. The hybrid membrane vesicle HMV integrates S. aureus membrane vesicles (SCMV), which provide homologous targeting and vaccine-like immunogenicity, with Lactococcus lactis vesicles (LMV), which contribute to anti-inflammatory immune regulation. This biomimetic coating enables a sequential targeting cascade: HMV first directs the nanoreactor toward MRSA-infected macrophages, and ROS-triggered membrane disassembly subsequently exposes cationic PEI-Fc to promote electrostatic binding to intracellular MRSA. After intracellular activation, cinnamaldehyde CA increases bacterial membrane permeability and depletes glutathione, while ferrocene Fc catalyzes endogenous H₂O₂ into hydroxyl radicals, thereby overwhelming bacterial antioxidant defenses and inducing catastrophic lipid peroxidation. This cascade-amplified ferroptosis-like antibacterial process efficiently eliminates intracellular MRSA. In parallel, the combined effects of bacterial ferroptosis and L. lactis vesicles promote macrophage polarization from the pro-inflammatory M1 phenotype toward the reparative M2 phenotype, suppress pro-inflammatory cytokines, with vaccine-like immunogenicity of SCMV, enhance anti-inflammatory cytokine production, and accelerate resolution of lung inflammation. By integrating pathogen-homing biomimetic delivery, cascade-responsive controlled release, ferroptosis-amplified antibacterial activity, and immune microenvironment remodeling, PCFP/CA@HMV provides a promising therapeutic strategy for refractory intracellular MRSA pneumonia. Download: Download high-res image (79KB) Download: Download full-size image