Molecular Therapy Nucleic Acids · Sep 18, 2026

Systemic and local delivery of siRNA to the CNS and periphery via anti-IGF1R antibody conjugation

By Tian M, Nikan M, Yoo M et al.

siRNA delivery platforms capable of accessing both central and peripheral tissues are critically needed to expand the therapeutic potential of oligonucleotides. To address this, we developed an siRNA-antibody conjugate by attaching an Hprt-targeting siRNA to an engineered antibody shuttle. This shuttle targets the insulin-like growth factor 1 receptor (IGF1R) using a fused antibody fragment (Clone F) and utilizes an antibody backbone with no tissue-relevant binding in this study. The resulting conjugate, designated Clone F-Hprt, demonstrated robust in vivo knockdown across multiple tissues. Clone F-Hprt demonstrated enhanced penetration into central nervous system (CNS) tissues compared to unconjugated siRNA following intracerebroventricular (ICV) and intravenous (IV) administration. In peripheral tissues, Clone F-Hprt achieved widespread knockdown in the muscle, heart, and lung, consistent with IGF1R expression. Under the conditions tested, no overt tolerability findings were observed based on home-cage behavior, body weight monitoring, and CNS inflammatory marker expression. The substantial progress of transferrin receptor (TfR)-targeted receptor-mediated delivery underscores the translational potential of blood-brain barrier (BBB) shuttle strategies and supports the exploration of complementary receptors such as IGF1R. Our findings highlight IGF1R as an alternative receptor capable of supporting delivery across both central and peripheral tissues, offering a complementary strategy for expanding the therapeutic landscape of oligonucleotide delivery.

doi.org/10.1016/j.omtn.2026.103105Open accessPubMed 42927339Interventions