Targeted Delivery of Oligonucleotide–Peptide Conjugates for Enhanced Kidney-Specific Therapy

Targeted drug delivery has emerged as a crucial strategy to enhance efficacy and minimize side effects from off-target interactions, a particularly relevant approach for kidney diseases, where many treatments suffer from poor targeting efficiency. In this study, we benchmarked a series of peptides previously identified for their kidney-targeting potential, utilizing them as targeting moieties for an oligonucleotide aimed at repressing HIF-1α expression in renal tubular cells. The peptides were synthesized, radiolabeled, and evaluated for their biodistribution profiles in mice. The best-performing peptide was conjugated to the oligonucleotide of interest, leveraging its kidney-targeting properties to optimize the delivery. We demonstrated that conjugation of the oligonucleotide to a kidney-targeting peptide preserved its repressing HIF-1α activity, while increasing accumulation 10-fold in the kidneys. The results from this study offer valuable insights into the potential of kidney-targeting peptides as a novel strategy to improve the efficacy and safety of therapies for kidney diseases.