Lipid-Modified Bilirubin Nanocrystals for the Repair of Ischemia-Reperfusion-Induced Acute Kidney Injury

Ischemia-reperfusion (IR)-induced acute kidney injury (AKI) is a life-threatening form of AKI frequently observed in clinical settings, such as hemorrhagic shock, kidney transplantation, and cardiovascular surgery. Targeting renal antioxidant therapy may represent an effective strategy against IR-induced AKI. Bilirubin (BR), a specific superoxide anion scavenger, faces limitations in clinical application due to its poor water solubility and hepatic metabolism pathway. In this study, we prepared bilirubin nanocrystals (BRNCs), which demonstrated potent antioxidant effects in vitro experiments. To enhance renal targeting, BRNCs were encapsulated in poly(ethylene glycol) (PEG)-modified lipid nanoparticle (BRNC-LNP). In vivo distribution studies revealed that BRNC-LNP effectively circumvented hepatic metabolism and exhibited enhanced renal accumulation compared to BRNC. In vivo efficacy evaluation revealed superior therapeutic outcomes with BRNC-LNP versus BRNC in AKI mice. These findings suggest that BRNC-LNP may serve as a promising therapeutic strategy for IR-induced AKI by reducing the level of hepatic metabolism and promoting renal targeting.