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.