An All‐in‐One Nano‐Biomimetic Polyamidoamine Dendrimer Platform for Treatment of CRKP Pneumonia

Abstract Polymyxin B (PMB) is often considered as the last line of defense for treating carbapenem‐resistant Klebsiella pneumoniae (CRKP). However, its efficacy is hindered by limited penetration across the blood‐air barrier in the lung due to its low lipid solubility. To simultaneously increase PMB in epithelial lining fluid while suppressing the excessive inflammatory response in the lung, a novel nano‐biomimetic system “Siv‐PMB@G4@MM” is designed and fabricated by encapsulating PMB‐ and anti‐inflammatory Sivelestat (Siv)‐loaded G4 PAMAM dendrimers with macrophage membranes (MM). The Siv‐PMB@G4@MM displayed a superior acidic pH‐responsive release property and can target inflamed lung tissues, greatly increasing the concentrations of PMB and Siv at the infection site. Compared with free drugs, Siv‐PMB@G4@MM demonstrated superior synergistic antibacterial and anti‐inflammatory activities. Moreover, due to the ability of MM to sequester lipopolysaccharide (LPS) and some pro‐inflammatory cytokines, Siv‐PMB@G4@MM further enhanced the anti‐inflammatory potential of Siv. In mouse models of LPS‐induced acute lung injury, pulmonary bacterial infection, and sepsis‐induced pneumonia, Siv‐PMB@G4@MM significantly reduced inflammatory responses and/or bacterial burdens, mitigated neutrophil infiltration and pulmonary edema, and decreased neutrophil extracellular trap (NET) secretion. The highly improved biocompatibility and efficiency of the multifunctional Siv‐PMB@G4@MM presents a promising strategy for the clinical treatment of antibiotic‐resistant bacterial pneumonia.