Reaching the CNS with therapeutic oligonucleotides via TfR1: navigating delivery and distribution challenges

Oligonucleotides have emerged as a major therapeutic modality, with several approved drugs and a growing pipeline. Historically, broader adoption was limited by poor tissue uptake, but advances in delivery technologies have largely overcome these barriers for hepatic targeting. However, extrahepatic delivery, particularly to the central nervous system (CNS), remains a significant challenge. Oligonucleotides cannot cross the blood–brain barrier (BBB) and are typically administered intrathecally, an invasive procedure often resulting in restricted distribution and suboptimal outcomes. Increasing interest in oligonucleotide therapies for CNS disorders has spurred efforts to enable systemic delivery. Oligonucleotide conjugation to vehicles leveraging transferrin receptor 1 (TfR1) for BBB crossing is emerging as a leading CNS delivery strategy. Given the brain’s extensive vascularization, this approach enables homogeneous distribution, reaching regions inaccessible via intrathecal injection. Here, we summarize the landscape of oligonucleotide therapies for CNS disorders and efforts to enable BBB crossing, with a focus on TfR1-based technologies.