TfR1-Binding Peptide Conjugation Facilitates Robust and Specific siRNA Delivery to the Central Nervous System.

Abstract

Transferrin receptor 1 (TfR1) is a ubiquitously expressed receptor characterized by rapid internalization kinetics and efficient receptor recycling, making it an attractive target for drug delivery. Herein, we investigated the potential of TfR1-binding peptide-siRNA conjugates for central nervous system (CNS)-specific gene silencing. A panel of TfR1-binding peptides and conjugation linkers were synthesized to enable siRNA attachment and evaluate their gene-silencing effects. Conjugation with the hTfR No. 894 peptide achieved effective siRNA delivery both in vitro and in vivo. Compared to ribose 2'-O-hexadecyl (C16)-siRNA conjugates, the hTfR No. 894-siRNA conjugation (POC2) elicited favorable pharmacokinetic characteristics and robust and durable silencing of the target gene across CNS regions following local administration, with minimal impact on peripheral tissues. These findings support TfR1-binding peptide conjugation as a promising strategy for CNS-targeted siRNA delivery.