Antioxidant and C5a-blocking strategy for hepatic ischemia\u2013reperfusion injury repair

Xiaobing Zhang,Dalong Ni,Shuping Qu,Kaelyn V Becker,Weibo Cai,Dong Wu,Jonathan W Engle,Jiajia Hu

doi:10.1186/s12951-021-00858-9

Abstract

BackgroundNonspecific liver uptake of nanomaterials after intravenous injection has hindered nanomedicine for clinical translation. However, nanomaterials’ propensity for liver distribution might enable their use in hepatic ischemia–reperfusion injury (IRI) repair. During hepatic IRI, reactive oxygen species (ROS) are generated and the fifth component of complement (C5a) is activated. In addition, C5a is confirmed to exacerbate the vicious cycle of oxidative stress and inflammatory damage. For these reasons, we have investigated the development of nanomaterials with liver uptake to scavenge ROS and block C5a for hepatic IRI repair.ResultsTo achieve this goal, a traditional nanoantioxidant of nanoceria was surface conjugated with the anti-C5a aptamers (Ceria@Apt) to scavenge the ROS and reduce C5a-mediated inflammation. High uptake of Ceria@Apt in the liver was confirmed by preclinical positron emission tomography (PET) imaging. The clinical symptoms of hepatic IRI were effectively alleviated by Ceria@Apt with ROS scavenging and C5a blocking in mice model. The released pro-inflammatory cytokines were significantly reduced, and subsequent inflammatory reaction involved in the liver was inhibited.ConclusionsThe synthesized Ceria@Apt has great potential of medical application in hepatic IRI repair, which could also be applied for other ischemic-related diseases.Graphic abstract

Highlights

Nanotechnology’s unique physiochemical properties portend a variety of useful medical applications [1,2,3,4]
We recently revealed the process of hepatic ischemia–reperfusion injury (IRI) repair by nanoceria, including reactive oxygen species (ROS) scavenging, inactivation of Kupffer cells, and inhibition of the recruitment and infiltration of neutrophils [28]
Synthesis and characterization of Ceria@Apt The nanoceria were synthesized and surface modified with DSPE-PEG5K-NH2 and DSPE-PEG5K according to the previous literature. [28, 47] As shown in transmission electron microscope (TEM) image (Fig. 1b), the synthesized nanoceria exhibited shape uniformity with 5 nm average diameter

Summary

Results

A traditional nanoantioxidant of nanoceria was surface conjugated with the anti-C5a aptamers (Ceria@Apt) to scavenge the ROS and reduce C5a-mediated inflammation. High uptake of Ceria@Apt in the liver was confirmed by preclinical positron emission tomography (PET) imaging. The clinical symptoms of hepatic IRI were effectively alleviated by Ceria@Apt with ROS scavenging and C5a blocking in mice model. The released proinflammatory cytokines were significantly reduced, and subsequent inflammatory reaction involved in the liver was inhibited

Conclusions

Introduction

Results and discussion

Conclusion