WuXi TIDES maps the path for oligonucleotides beyond the liver

GalNAc conjugation has given the oligonucleotide field a reliable, clinically validated route into hepatocytes, underpinning multiple approved siRNA medicines and a broad pipeline of liver-directed therapies. But the sector's next growth frontier lies further afield: skeletal and cardiac muscle, the central nervous system, the lungs, and immune cells, each of which presents a distinct set of biological barriers that GalNAc cannot address.

WuXi AppTec, the contract research, development and manufacturing organisation (CRDMO), has published a technical analysis through its WuXi TIDES division examining how early delivery choices for extrahepatic oligonucleotide programmes cascade through the entire development architecture, affecting biodistribution, dosing frequency, safety margins, analytical methods, formulation, and manufacturing complexity.

Tissue-by-tissue engineering challenges

The release outlines four target tissues that are attracting particular attention, and the challenges each presents.

For muscle, researchers are attaching oligonucleotides to antibodies or peptides that bind the transferrin receptor 1 (TfR1), which is expressed on muscle cells and undergoes internalisation. Preclinical antibody-oligonucleotide conjugate (AOC) programmes have reportedly demonstrated substantially greater uptake in skeletal and cardiac muscle than unconjugated molecules, and several are said to have entered late-stage clinical development.

Neurological oligonucleotides such as nusinersen and tofersen bypass the blood-brain barrier through intrathecal delivery, but systemic CNS targeting remains at an earlier stage. Researchers are engineering conjugate systems that exploit endogenous transport pathways, including the transferrin receptor, to carry payloads across the barrier; broader brain exposure has been demonstrated in preclinical models, though clinical validation is limited.

The lung can, in principle, be approached from either side. Inhaled formulations place nucleic-acid constructs directly into the respiratory tract, but a formulation must survive aerosolisation, penetrate mucus, and reach the relevant epithelial or immune-cell population. Systemic approaches face the competing pull of hepatic distribution. For immune cells, lipid nanoparticles whose composition or surface ligands are tuned to specific populations, T cells, macrophages or dendritic cells, are among the leading strategies.

Manufacturing complexity scales with delivery ambition

Yu Lu, Senior Vice President at WuXi TIDES, said the field should not expect a single platform to solve extrahepatic delivery across all tissues. "The companies that can connect targeting biology, molecular design, analytics and scalable manufacturing will be best positioned to turn extrahepatic delivery from promising science into effective therapeutics," he said.

The manufacturing point is significant. Conjugated oligonucleotides require processes that maintain conjugation efficiency at scale, purification methods capable of separating the desired product from unconjugated or partially reacted species, and analytical tools that can characterise a multicomponent molecule comprising oligonucleotide strand, linker, and targeting moiety as an integrated product. Lipid nanoparticle programmes layer in additional demands around lipid synthesis, particle characterisation, aerodynamic properties where inhalation is involved, and sterile fill-finish.

The broader competitive landscape reflects these manufacturing pressures. Several dedicated oligonucleotide CDMOs, as well as in-house capacity at large pharma groups, are competing for extrahepatic programmes. The complexity of conjugate and nanoparticle manufacture is pushing sponsors toward integrated platforms to avoid costly technology transfers across vendors, a dynamic that favours CRDMOs with end-to-end chemistry, analytical, and manufacturing capabilities. Regulatory agencies have also signalled closer scrutiny of oligonucleotide impurity control, sequence integrity, and stability data as the modality matures, raising the analytical bar for programmes moving into clinical development.

WuXi AppTec operates across more than 30 countries and positions its TIDES platform as covering oligonucleotide, peptide, linker, ligand, lipid and PEG chemistry within a single integrated offering. The company did not announce a specific new partnership, programme, or funding event in connection with this release.