Reactive oxygen species-generating hydrogel platform for enhanced antibacterial therapy

Abstract Zinc oxide nanoparticles (ZnO) have attracted much attention as promising antibacterial agents due to their ability to generate reactive oxygen species (ROS) that effectively eliminate bacteria. However, when they are delivered inside the body, this distinct characteristic of ROS is restricted due to the limited penetration depth of external light, which is required for the photocatalysis of particles. To produce ROS without any light source when the particles are implanted, we introduced catechol-ZnO complexes to a hyaluronic acid (HA) hydrogel platform, which can self-generate sufficient ROS in the bacteria-infected tissue. Catechol-ZnO complexes enhanced ROS generation via electron transfer from the formation of complexes and o-semiquinone, and a hydrogel structure was created by coordinate bonds between functionalized catechol groups in HA and ZnO simultaneously. This hydrogel demonstrated different behaviors in terms of physical properties compared to chemically cross-linked HA hydrogels containing ZnO. This hydrogel showed a higher swelling ratio, enzymatic degradation resistance, and tissue adhesive strength. Enhanced ROS generation was confirmed using electron paramagnetic resonance (EPR), H₂O₂ concentration, glutathione depletion, and intracellular ROS detection. The improved antibacterial performance of hydrogels from ROS production was also confirmed through in vitro bacterial testing against two bacterial strains, E. coli and S. aureus. Furthermore, an in vivo experiment using an infected mouse model to analyze colony formation, histologic analysis, and hematological inflammatory markers revealed the effective antibacterial effects of catechol-ZnO complexes. Overall, the potential of the hydrogel created via catechol-ZnO complexes for antibacterial therapy was demonstrated through the capability to enhance ROS generation and eradicate bacteria.