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.