pH-Responsive non-antibiotic polymer prodrugs eradicate intracellular infection by killing bacteria and regulating immune response.

Intracellular bacterial infections pose enormous challenges to food safety and public health. Antibiotic-based polymer prodrugs have been used to treat intracellular bacterial infection. However, the overuse of antibiotics may lead to the emergence of antibiotic resistance. In this work, we aimed to develop antibiotic-free pH-responsive polymeric prodrugs to combat intracellular S. aureus infection. Amphiphilic poly(ethylene glycol)-b-poly[(3-phenylprop-2-ene-1,1-diyl)bis(oxy)bis(enthane-2,1- diyl)diacrylate] (PEG-b-PCAE) was obtained by radical polymerization and they could self-assemble to form micelles. PEG-b-PCAE micelles could uptake by macrophage. Upon exposure to the acidic phagolysosome, PEG-b-PCAE micelles could release cinnamaldehyde (CA) through hydrolysis of the acetal linkage. PEG-b-PCAE could kill intracellular bacteria by damaging the bacterial membrane. Furthermore, PEG-b-PCAE micelles could generate reactive oxygen species (ROS) in macrophages and subsequently activate immune system to clear bacteria by inducing macrophages differentiation to M1 phenotype. PEG-b-PCAE micelles could accelerate the wound healing process of the S. aureus-infected model in vivo. It is anticipated that multifunctional antibiotic-free PEG-b-PCAE micelles with intrinsic antibacterial activities hold promise for improved outcomes in intracellular S. aureus infections.