The LiCO platform: A novel benzimidazole-based lipid conjugate for versatile and sustained siRNA delivery beyond the liver
- 1Ractigen Therapeutics, Nantong, Jiangsu, China
- 2Ractigen Therapeutics, Nantong, Jiangsu, China; Corresponding author: Long-Cheng Li, Ractigen Therapeutics, 4th floor, Bldg.1, BioBay 3B, Suzhou Industrial Park, 99 Jingu Rd, Suzhou, Jiangsu Province 215000, China
Abstract
Extending oligonucleotide therapeutics beyond the liver remains a central challenge for RNA medicine. Here, we describe a lipid-conjugated oligonucleotide (LiCO), a benzimidazole-enabled lipid-duplex RNA conjugate platform synthesized as a single chemical entity by standard solid-phase chemistry. Structure-activity screening identified a 5′-passenger-strand hexadecyl (C16) conjugate whose benzimidazole (SDL) linker markedly improved delivery activity relative to a linker-free analog, and studies in CD36-knockout mice established CD36-dependent uptake as the principal driver of extrahepatic tropism. A single systemic dose in mice produced >90% target knockdown in skeletal muscle, heart, aorta, and adipose tissue, with ≥50% silencing persisting for 6 months and measurable activity at 9 months, whereas hepatic silencing was transient. In cynomolgus macaques, two intravenous doses of LiCO-siMSTN achieved ∼90% myostatin mRNA knockdown, 60%–70% suppression of circulating myostatin protein through day 98, and progressive muscle hypertrophy without adverse clinical, hematological, or biochemical findings. In situ hybridization confirmed deep penetration of myofibers, myocardium, and aortic smooth muscle. LiCO also enabled potent local delivery to the synovium, retina, and bladder with minimal systemic exposure. LiCO offers a scalable, versatile platform for neuromuscular, metabolic, and localized disorders.
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BibTeX
@article{kang2026lico,
title = {{The LiCO platform: A novel benzimidazole-based lipid conjugate for versatile and sustained siRNA delivery beyond the liver}},
author = {Moorim Kang and Zubao Gan and Qifeng Ding and Wei-Hsiang Lin and Jie Wang and Feifei Xu and Xiaojie Zhou and Ke Lu and Vera Huang and Long-Cheng Li},
journal = {Molecular Therapy: Nucleic Acids},
year = {2026},
month = nov,
doi = {10.1016/j.omtn.2026.103154},
url = {https://doi.org/10.1016/j.omtn.2026.103154},
note = {CC BY},
}
RIS
TY - JOUR
TI - The LiCO platform: A novel benzimidazole-based lipid conjugate for versatile and sustained siRNA delivery beyond the liver
AU - Moorim Kang
AU - Zubao Gan
AU - Qifeng Ding
AU - Wei-Hsiang Lin
AU - Jie Wang
AU - Feifei Xu
AU - Xiaojie Zhou
AU - Ke Lu
AU - Vera Huang
AU - Long-Cheng Li
PY - 2026
DA - 2026/11/06
JO - Molecular Therapy: Nucleic Acids
DO - 10.1016/j.omtn.2026.103154
UR - https://doi.org/10.1016/j.omtn.2026.103154
AB - Extending oligonucleotide therapeutics beyond the liver remains a central challenge for RNA medicine. Here, we describe a lipid-conjugated oligonucleotide (LiCO), a benzimidazole-enabled lipid-duplex RNA conjugate platform synthesized as a single chemical entity by standard solid-phase chemistry. Structure-activity screening identified a 5′-passenger-strand hexadecyl (C16) conjugate whose benzimidazole (SDL) linker markedly improved delivery activity relative to a linker-free analog, and studies in CD36-knockout mice established CD36-dependent uptake as the principal driver of extrahepatic tropism. A single systemic dose in mice produced >90% target knockdown in skeletal muscle, heart, aorta, and adipose tissue, with ≥50% silencing persisting for 6 months and measurable activity at 9 months, whereas hepatic silencing was transient. In cynomolgus macaques, two intravenous doses of LiCO-siMSTN achieved ∼90% myostatin mRNA knockdown, 60%–70% suppression of circulating myostatin protein through day 98, and progressive muscle hypertrophy without adverse clinical, hematological, or biochemical findings. In situ hybridization confirmed deep penetration of myofibers, myocardium, and aortic smooth muscle. LiCO also enabled potent local delivery to the synovium, retina, and bladder with minimal systemic exposure. LiCO offers a scalable, versatile platform for neuromuscular, metabolic, and localized disorders.
SN - 2162-2531
ER -