Inhaled pH-Responsive polymyxin B-loaded albumin nanoparticles against pneumonia caused by carbapenem resistant Klebsiella pneumoniae

The pneumonia induced by carbapenem resistant <i>Klebsiella pneumoniae</i> (CRKP) has high morbidity and mortality. Among the antibiotics currently available, polymyxin B (PMB) is considered to be the last line of defense. Routine intravenous administration of PMB has many problems, such as severe neurotoxicity and nephrotoxicity. In this study, a novel inhaled PMB-loaded albumin nanoparticles (PEG-pHSA@PMB) capable of penetrating airway mucus and responding to the infection microenvironment is constructed. An acid-responsive functional molecule (PEBA) and NH₂-PEG-SH are linked to the surface of human serum albumin (HSA) via the conjugation reaction. Subsequently, PMB is loaded through electrostatic interactions to yield PEG-pHSA@PMB. The sulfhydryl groups of PEG-pHSA@PMB interact with mucins to help penetrate mucus after inhaled. In an acidic environment, the protonation of the tertiary amino groups within PEG-pHSA@PMB causes the charge alteration, which leads to the release of PMB. It demonstrated excellent mucus permeability, potent bactericidal activity, and superior bacteriostatic effects compared to sole PMB. Inhalation of PEG-pHSA@PMB significantly reduced the bacterial load in the lungs of mice with CRKP pneumonia, alleviating inflammatory response. Moreover, PEG-pHSA@PMB exhibited good cytocompatibility and biosafety. The novel strategy of the inhalation drug delivery system is promising for the treatment of pneumonia caused by drug-resistant bacteria.