Neuraminidase and nitric oxide dual response via PSA-PLGA nanoparticles: A novel approach for controlling Glaesserella parasuis inflammation and infection.

The overexpression of virulence factors and the induced inflammatory cytokine storm, resulting in tissue damage, represent significant challenges in treating antibiotic-resistant bacterial infections with conventional antibiotics. Herein, we have developed a bifunctional nanoparticle loaded with antibiotics (PSA@PLGA-TD/SMT) designed for precise response to the virulence proteins of drug-resistant bacteria while protecting the host from excessive inflammatory damage. This is achieved by modifying polylactic-co-glycolic acid (PLGA) nanoparticles with polysialic acid (PSA). Tildipirosin (TD), through hydrophobic interactions, is encapsulated within the core, while S-Methylisothiourea (SMT) is electrostatically adsorbed onto the shell layer. In vitro, the polysialic acid in the nanoparticles interacts with the neuraminidase overexpressed on the surface of Glaesserella parasuis (Gps), triggering disintegration and subsequent release of TD, which effectively kills the bacteria. Additionally, SMT functions to suppress the secretion of inducible nitric oxide synthase (NOS2), promoting the phenotypic transformation of macrophages and reducing the expression of pro-inflammatory factors. Ultimately, PSA@PLGA-TD/SMT achieves an extended drug circulation time through its prolonged retention effect, effectively alleviating discomfort caused by resistant bacteria. Therefore, the construction of nanocarriers for precise targeting of drug-resistant pathogens, delivering antibiotics, and preventing host-induced inflammatory damage presents an effective treatment strategy. This approach not only addresses the direct issue of bacterial eradication but also mitigates the collateral damage typically associated with severe infections, offering a more comprehensive and nuanced approach to managing drug-resistant bacterial infections.