Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

Treatments that target single mediators of sepsis have failed to reduce its high mortality rate. Here we developed multifunctional tannic acid-Zn2+-gentamicin nanoparticles (TA-Zn-Gen NPs) that target multiple mediators of sepsis to improve sepsis treatment. TA-Zn-Gen NPs with lower gentamicin content possessed net negative surface charge but still bound cell-free DNA (cfDNA) with high affinity. The TA-Zn-Gen NPs exhibited five modes of anti-sepsis activity: (1) scavenged cfDNA and inhibited cfDNA-initiated activation of toll-like receptors and NF-κB signaling; (2) inhibited activated macrophage-induced macrophage recruitment; (3) scavenged reactive oxygen species (ROS) and reduced ROS-induced DNA damage and cell death; (4) inhibited nitric oxide production induced by lipopolysaccharides; and (5) potent antibacterial activity. The NPs reduced multiple organ damage and increased the survival rate of mice with severe sepsis. Together, the results demonstrate the potency of targeting multiple mediators for sepsis treatment, and support the development of multifunctional NPs for treating other intractable inflammation-related diseases.