Inulin-based nanoparticles for targeted siRNA delivery in acute kidney injury

Abstract

RNA interference has emerged as a promising therapeutic strategy to tackle acute kidney injury (AKI). Development of targeted delivery systems is highly desired for selective renal delivery of RNA and improved therapeutic outcomes in AKI. Inulin is a plant polysaccharide traditionally employed to measure glomerular filtration rate. Here, we describe the synthesis of inulin modified with α-cyclam-p-toluic acid (CPTA) to form a novel renal-targeted polymer, Inulin-CPTA (IC), which is capable of selective siRNA delivery to the injured kidneys. We show that conjugating CPTA to inulin imparts IC with targeting properties for cells that overexpress the C-X-C chemokine receptor 4 (CXCR4). Self-assembled IC/siRNA nanoparticles (polyplexes) demonstrated rapid accumulation in the injured kidneys with selective uptake and prolonged retention in injured renal tubules overexpressing the CXCR4 receptor. Tumor-suppressor protein p53 contributes significantly to the pathogenesis of AKI. siRNA-induced silencing of p53 has shown therapeutic potential in several preclinical studies, making it an important target in the treatment of AKI. Systemically administered nanoparticles formulated using IC and siRNA against p53 selectively accumulated in the injured kidneys and potently silenced p53 expression. Selective p53 knockdown led to positive therapeutic outcomes in mice with cisplatin-induced AKI, as seen by reduced tubular cell death, renal injury, inflammation, and overall improved renal function. These findings indicate that IC is a promising new carrier for renal-targeted delivery of RNA for the treatment of AKI.