M2 macrophage-mediated tigecycline nanoparticles for combating CRKP pneumonia via antibacterial and immunomodulatory therapy

Abstract

Pneumonia caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) has a high mortality rate and exhibits multiple drug resistance, making current antibacterial treatments of limited efficacy. To address the challenges of ineffective drug accumulation at the infection site and excessive inflammation leading to tissue damage, this study developed a cell-based nano-bionic drug delivery system (denoted as PT@M2, PLGA-TIG nanoparticles loaded into M2 macrophages). This system encapsulates poly(lactic-co-glycolic acid) (PLGA) loaded with tigecycline within M2-type macrophages, thereby achieving stable circulation, rapid release in acidic microenvironments, and targeted delivery to the lungs. In vitro experiments showed that PT@M2 significantly reduced the minimum inhibitory concentration of CRKP, disrupted bacterial membranes, and induced reactive oxygen species accumulation. In a mouse pneumonia model, PT@M2 effectively reduced bacterial colonies, alleviated inflammatory responses, and improved pulmonary histopathology. Wefurther confirmed that PT@M2 could inhibit calcium ion influx by downregulating CACNG6, thereby indirectly modulating the MAPK pathway. In summary, PT@M2 enhances antibacterial efficacy through a dual mechanism of "bactericidal action + immune microenvironment remodeling," providing a novel therapeutic strategy for the treatment of multidrug-resistant bacterial infections.

Keywords: Biomimetic nano-drug delivery system; Carbapenem-resistant Klebsiella pneumoniae (CRKP); M2 macrophages; Pneumonia; Tigecycline (TIG).