pH-Responsive Hyperbranched Polymer Nanoparticles to Combat Intracellular Infection by Disrupting Bacterial Wall and Regulating Macrophage Polarization.

Intracellular bacterial infections pose a serious threat to public health. Macrophages are a heterogeneous population of immune cells that play a vital role in intracellular bacterial infection. However, bacteria that survive inside macrophages could subvert the cell signaling and eventually reduce the antimicrobial activity of macrophages. Herein, dual pH-responsive polymer (poly[(3-phenylprop-2-ene-1,1-diyl)bis(oxy)bis(enthane-2,1-diyl)diacrylate-co--aminoethylpiperazine] (PCA)) nanoparticles were developed to clear intracellular bacteria by activating macrophages and destructing bacterial walls. The presence of acid-labile acetal linkages and tertiary amine groups in the polymer's backbone endow hyperbranched PCA dual pH-response activity that shows acid-induced positive charge increase and cinnamaldehyde release properties. The biodegraded PCA nanoparticles could significantly inhibit the growth of bacteria by damaging the bacterial walls. Meanwhile, PCA nanoparticles could uptake by macrophages, generate reactive oxygen species (ROS), and remodel the immune response by upregulating M1 polarization, leading to the reinforced antimicrobial capacity. Furthermore, PCA nanoparticles could promote bacteria-infected wound healing in vivo. Therefore, these dual pH-responsive PCA nanoparticles enabling bacteria-killing and macrophage activation provide a novel outlook for treating intracellular infection.