Self‐Propelled Lung‐Targeting Nanovaccine Modulates Iron Homeostasis‐Immune Crosstalk for Therapeutic‐Prophylactic Intervention in Bacterial Pneumonia

Abstract The iron homeostasis‐immune crosstalk within bacterial infection microenvironments critically challenges pathogen clearance and prophylactic efficacy. Herein, a self‐propelled nanovaccine (Algae‐FeMSN/LEV@OMV) is presented, comprising motile C. reinhardtii functionalized with maltotriose and iron homeostasis‐regulated nanoparticles coated with P. aeruginosa ‐derived outer membrane vesicles (OMVs). This system demonstrates targeted delivery to deep‐infected tissues, such as pulmonary infection sites, effectively penetrating the pulmonary mucus barrier while enabling prolonged retention at pathological sites. The OMVs, which encapsulate levofloxacin (LEV)‐loaded mesoporous iron silicate nanoparticles (FeMSN/LEV@OMV), restore iron‐depleted infection microenvironments (29.05 µmol L −1 vs 17.03 µmol L −1 in infected mice) to modulate iron homeostasis‐immune crosstalk, thereby potently eliciting innate and adaptive immunity. Synergizing with LEV's immediate bactericidal action, this approach prevents iron‐mediated infection exacerbation, enabling sustained‐effective (28 day) therapy and prevention for bacterial pneumonia in mice. Algae‐FeMSN/LEV@OMV enhances in vivo antibacterial efficacy through superior bacterial affinity and site retention compared to free LEV, achieving pathogen eradication with reduced antibiotic dosage (2.0 µg vs 0.6 mg clinical‐grade LEV). This actively motile biohybrid system overcomes premature nanovaccine clearance in vivo, rectifies infection‐induced iron dyshomeostasis, and concurrently realizes therapeutic‐prophylactic synergy against bacterial pneumonia. Together, Algae‐FeMSN/LEV@OMV represents a valuable strategy for addressing clinical challenges in antibiotic utilization.