Kidney targeted delivery of siRNA mediated by peptide-siRNA conjugate for the treatment of acute kidney injury

Small interfering RNA (siRNA), a promising revolutionary therapy, faces delivery obstacles due to its poor targeting, strong charge negativity and macromolecular nature. Clinical-approved siRNAs can now only be delivered to the liver mediated by the chemically conjugated N-acetylgalactosamine (GalNAc) ligand, the conjugate can be effectively uptaken into cells through interaction with asialoglycoprotein receptor (ASGPR) highly expressed on liver hepatocytes. To further explore an efficient non-hepatic targeted delivery strategy, in this study, we designed a delivery system that chemically conjugated p53 siRNA to renal tubular cell-targeting peptides for targeting the kidney, which was suitable for industrial transformation. Results showed that peptide-siRNA conjugate could specifically enter renal tubular epithelial cells and silence target genes. In cisplatin-induced acute kidney injury (AKI) mice, peptide-siRNA conjugate blocked the p53-mediated apoptotic pathway and alleviated renal damage. The innovative proposed system to conjugate kidney-targeting peptides with siRNA achieved the efficient kidney-targeted delivery of siRNA and provided a prospective choice for treating AKI.