Paricalcitol-loaded PLGA nanodrug for the amelioration of sepsis-associated acute kidney injury

• Paricalcitol was efficiently loaded into PLGA with high encapsulation efficiency. • PLGA@pari NPs showed significant renal accumulation and markedly prolonged half-life. • PLGA@pari NPs exhibited anti-inflammatory, ROS-scavenging and anti-apoptotic effects, ameliorating SA-AKI. • PLGA@pari NPs had high clinical potential due to simple preparation, biocompatibility and biosafety. Sepsis-associated acute kidney injury (SA-AKI) is a severe clinical condition with a high mortality. Currently, there is no specific therapy for SA-AKI, and clinicians can only rely on extensive supportive treatment. Therefore, finding effective methods for SA-AKI therapy is crucial to delay the progression of sepsis. Our previous studies have found that paricalcitol, an active vitamin D analog, can reduce renal inflammation and delay the progression of SA-AKI. However, expression inhibition of megalin caused by endotoxins can reduce the entry of active vitamin D into renal tubular epithelial cells and weakening its renal protective efficacy. Therefore, how to enhance the enrichment of paricalcitol in the kidney is a challenge. In this study, we constructed a nanodrug delivery system to enhance the enrichment of paricalcitol in the kidney by encapsulating paricalcitol into a poly lactic-co-glycolic acid (PLGA) nanosystem, forming PLGA@paricalcitol nanoparticles (PLGA@pari NPs). In vivo experiments demonstrated that PLGA@pari NPs exhibited higher accumulation in the kidneys and significantly improve renal function in septic mice. The study indicates that PLGA@pari NPs represent a simple, safe, and efficient drug delivery system that enhances the therapeutic efficacy for SA-AKI by improving renal accumulation. This study provides new insights for clinical treatment of SA-AKI.