H₂O₂-Activatable Antioxidant Polymeric Prodrug Nanoparticles for the Prevention of Renal Ischemia/Reperfusion Injury

Renal ischemia-reperfusion (IR) injury is an inevitable complication in various clinical settings including kidney transplantation and major vascular surgeries. Renal IR injury is a major risk factor for acute kidney injury, which still remains a major clinical challenge without effective therapy. The main cause of renal IR injury is the massive production of reactive oxygen species (ROS) including hydrogen peroxide (H₂O₂) that initiate inflammatory signaling pathways, leading to renal cell death. In this study, we developed fucoidan-coated polymeric prodrug (Fu-PVU73) nanoparticles as renal IR-targeting nanotherapeutics that can rapidly eliminate H₂O₂and exert anti-inflammatory and antiapoptotic effects. Fu-PVU73 nanoparticles were composed of H₂O₂-activatable antioxidant and anti-inflammatory polymeric prodrug (PVU73) that incorporated H₂O₂-responsive peroxalate linkages, ursodeoxycholic acid (UDCA), and vanillyl alcohol (VA) in its backbone. Fu-PVU73 nanoparticles rapidly scavenged H₂O₂and released UDCA and VA during H₂O₂-triggered degradation. In the study of renal IR injury mouse models, Fu-PVU73 nanoparticles preferentially accumulated in the IR injury-induced kidney and markedly protected the kidney from IR injury by suppressing the generation of ROS and the expression of proinflammatory cytokines. We anticipate that Fu-PVU73 nanoparticles have tremendous therapeutic potential for not only renal IR injury but also various ROS-associated inflammatory diseases.