Neutrophil-Mimetic oleanolic acid-loaded Liposomes targeted to alleviate oxidative stress for renal ischemia-reperfusion injury treatment

Acute kidney injury (AKI) is a prevalent clinical condition characterized by a sudden decline or loss of renal function, exacerbated by the lack of effective diagnostic and therapeutic tools. Renal ischemia-reperfusion injury serves as the primary cause of AKI, initiating a complex signaling cascade that mediates renal cell necrosis, apoptosis, and inflammation. Oxidative stress plays a crucial role in the pathogenesis and progression of ischemia-reperfusion injury, thus prompting the exploration of antioxidants as potential therapeutic interventions. Oleanolic acid, derived from natural plant extracts, exhibits significant antioxidant and anti-inflammatory properties; however, its clinical application has been hindered by inherent limitations such as poor water solubility and low bioavailability. To address this issue, we developed an innovative approach involving oleanolic acid-loaded liposomes fused with neutrophil membranes, resulting in hybrid liposomes (N-OAL). This strategy aims to enhance the accumulation and retention of N-OAL at inflammatory sites associated with AKI through biomimetic chemotaxis mediated by neutrophil membranes specifically targeting damaged renal tubular epithelial cells. The optimized N-OAL presented a spherical morphology with an average particle size of 125.6 ± 4.9 nm and a surface potential of −4.8 ± 0.3 mV. In addition, N-OAL exhibited favorable sustained release, outstanding stability, and satisfactory biocompatibility. In vitro studies demonstrated that N-OAL effectively attenuated H₂O₂-induced intracellular reactive oxygen species generation and inflammation while exhibiting superior antioxidant and anti-apoptotic properties. Furthermore, our in vivo results confirmed the remarkable protective effect of N-OAL on oxidative-damaged renal tissue caused by AKI induction. Overall, our study provides novel insights into targeted delivery strategies for oleanolic acid therapy in acute kidney injury.