Polycationic nanoparticles for cascaded antibiosis and LPS- detoxifying via co-delivery of antibiotics and TLR siRNA in bacterial infected diseases treatment

Antimicrobial-resistant (AMR) Gram-negative bacteria emerge due to the overuse of antibiotics. Moreover, current bactericidal drugs or materials inevitably associate with the immunologic risks from the lipopolysaccharide (LPS) released by dead bacteria, which initiates and exacerbates chronic tissue-destructive hyperinflammation, leading to treatment failure. In this study, we describe an orchestrated pH-sensitive cationic polymer nanoparticle encapsulated with rifampicin and toll-like receptor (TLR) siRNA (RNP/siRNA) that exhibits antibacterial and LPS-detoxifying characteristics for treating infected diseases. Under acidic conditions, RNP/siRNA nanoparticle releases rifampicin and cationic polymers displaying synergistically inhibitory activity against AMR bacteria by disrupting bacterial membranes, and facilitating the entry of antibiotics. Furthermore, RNP/siRNA nanoparticle exhibits high cellular uptake and TLR knockdown efficiency, thereby detoxifying the etiological LPS in M1-type macrophages polarization and reducing proinflammatory cytokines. In a mouse pneumonia model, RNP/siRNA nanoparticle treatment inhibits bacterial growth, suppresses inflammation and reduces leukocyte recruitment. In a rat periodontitis model, the administration of RNP/siRNA downregulates proinflammatory cytokines expression and inhibits bone resorption. This work highlights the elevated LPS release is an early trigger of hyperinflammation during the antibacterial process of currently established antimicrobials. The RNP/siRNA nanoparticle represents a promising strategy by integrating antibiosis and immunomodulation in a cascading manner for the treatment of bacterial infections.