Will the Revolution Be Cyclized?: Using Macrocyclic Peptides to Deliver Oligonucleotides Extrahepaticaly

Abstract Oligonucleotide therapeutics have achieved reliable hepatic delivery, but extrahepatic delivery to muscle, CNS, and other targets has largely depended on bulky antibody-oligonucleotide conjugates targeting the transferrin receptor 1 (TfR1). A recent Ionis/Bicycle Therapeutics report instead conjugates ASO and siRNA payloads to an optimized macrocyclic peptide (BCY17901) that binds TfR1 with high affinity at a site distinct from the native transferrin epitope. In TfR1 knock-in mice, this peptide–oligonucleotide conjugate matched antibody-fragment-level knockdown despite being ∼ 25-fold smaller, while sparing the liver and enabling subcutaneous dosing. We review the area of extrahepatic oligonucleotide delivery and discuss how the new results position macrocyclic peptides as a compact, synthetically accessible alternative to antibodies for such applications.