Coating of a Novel Antimicrobial Nanoparticle with a Macrophage Membrane for the Selective Entry into Infected Macrophages and Killing of Intracellular Staphylococci

Abstract

Internalization of <i>Staphylococcus aureus</i> by macrophages can inactivate bacterial killing mechanisms, allowing intracellular residence and dissemination of infection. Concurrently, these staphylococci can evade antibiotics that are frequently unable to pass mammalian cell membranes. A binary, amphiphilic conjugate composed of triclosan and ciprofloxacin is synthesized that self-assemble through micelle formation into antimicrobial nanoparticles (ANPs). These novel ANPs are stabilized through encapsulation in macrophage membranes, providing membrane-encapsulated, antimicrobial-conjugated NPs (Me-ANPs) with similar protein activity, Toll-like receptor expression and negative surface charge as their precursor murine macrophage/human monocyte cell lines. The combination of Toll-like receptors and negative surface charge allows uptake of Me-ANPs by infected macrophages/monocytes through positively charged, lysozyme-rich membrane scars created during staphylococcal engulfment. Me-ANPs are not engulfed by more negatively charged sterile cells possessing less lysozyme at their surface. The Me-ANPs kill staphylococci internalized in macrophages in vitro. Me-ANPs likewise kill staphylococci more effectively than ANPs without membrane-encapsulation or clinically used ciprofloxacin in a mouse peritoneal infection model. Similarly, organ infections in mice created by dissemination of infected macrophages through circulation in the blood are better eradicated by Me-ANPs than by ciprofloxacin. These unique antimicrobial properties of macrophage-monocyte Me-ANPs provide a promising direction for human clinical application to combat persistent infections.