Caffeic Acid-Functionalized Poly- l -Ornithine Nanoparticles for Treatment of Bacterial Pneumonia

Abstract Bacterial pneumonia poses a serious threat to human health. Current therapeutic strategies for infectious pneumonia typically prioritize enhancing bactericidal efficacy. However, the excessive pulmonary inflammatory response during bacterial pneumonia often aggravates lung tissue injury and delays recovery. Therefore, the development of therapeutic agents with both antibacterial and anti-inflammatory activities is of great significance for the treatment of pneumonia. In this study, a series of cationic poly(l-ornithine)s (PLOs) with different degrees of caffeic acid (CA) modification were synthesized and evaluated for the treatment of bacterial pneumonia. Among all the polymers, PLO@CA(20%) exhibited the best antibacterial activity, with a minimum inhibitory concentration (MIC) of 2.5 μg/mL against Staphylococcus aureus. Mechanistic studies revealed that PLO@CA(20%) effectively binds to the negatively charged phospholipid phosphatidylglycerol (POPG) in the bacterial membrane, thereby disrupting membrane integrity and inducing bacterial death. Notably, PLO@CA(20%) showed favorable in vitro anti-inflammatory activity by effectively reducing reactive oxygen species (ROS) levels in lipopolysaccharide-stimulated macrophages. In a mouse model of bacterial pneumonia, PLO@CA(20%) effectively reduced lung bacterial burden, suppressed inflammatory cytokines, and significantly prolonged survival compared with the antibiotic and PLO groups. This combined antibacterial and inflammation-resolving strategy therefore outperformed monotherapy focused solely on bacterial eradication.