- Beyond-liver delivery is becoming the next major frontier for oligonucleotide medicines, with growing efforts to reach muscle, the central nervous system, lung, immune cells and tumors.
- No single delivery technology is likely to work across all tissues. Antibody conjugates, peptides, lipid conjugates and targeted nanoparticles are being tailored to specific receptors, cell types and biological barriers.
- Delivery strategy shapes the entire downstream program, influencing biodistribution, dose and dosing frequency, safety margins, bioanalytical needs, formulation, impurity control and manufacturing complexity.
San Diego, CA, Sept. 03, 2026 (GLOBE NEWSWIRE) -- For oligonucleotide medicines, precise delivery remains one of the field’s most important priorities. The liver has become an established target for systemic delivery, with GalNAc conjugation providing a clinically validated route into hepatocytes and continuing to support new therapeutic programs. The challenge now is to extend that level of delivery precision to tissues such as skeletal and cardiac muscle, the central nervous system, the lungs, immune cells, and tumors. Because the relevant receptor biology, cellular barriers, and delivery requirements differ substantially across these tissues, developers are exploring antibody, peptide, and other conjugation strategies alongside targeted nanoparticles rather than relying on a single technology. Each approach carries different implications for biodistribution, dose, safety, analytics, formulation, and manufacturing. WuXi AppTec, a contract research, development, and manufacturing organization (CRDMO) that works as an enabling partner to biotech and pharmaceutical innovators across more than 30 countries, has been tracking how these early delivery choices can reshape a program when the target tissue is no longer the liver.
"Moving beyond the liver will not depend on one universal solution, but on solving the distinct biological and delivery challenges of each tissue," said Yu Lu, Senior Vice President, WuXi TIDES, part of WuXi AppTec. "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."
Liver-Targeted Conjugation Established a Reproducible Delivery Model
The liver became the first major proving ground for systemic oligonucleotide delivery because hepatocytes express high levels of the asialoglycoprotein receptor (ASGPR). GalNAc conjugates are designed to bind that receptor and enter hepatocytes through receptor-mediated endocytosis after subcutaneous administration. The result is a compact, chemically defined drug construct that can reach its target tissue without requiring a separate nanoparticle carrier. Over time, this combination created a reproducible development model spanning conjugate synthesis, purification, analytical characterization, formulation, and subcutaneous dosing, and it has supported multiple approved siRNA medicines as well as a growing pipeline of liver-directed therapies.
Muscle, the Central Nervous System, the Lungs and Immune Cells Each Present a Different Delivery Problem
Outside the liver, there is no equivalent of GalNAc–ASGPR that can simply be applied across tissues. Each organ presents a different combination of receptor expression, cellular uptake and intracellular trafficking, which means extrahepatic delivery is developing as a collection of tissue-specific strategies rather than a single one.
Muscle is one of the clearest examples of receptor-mediated delivery. Skeletal and cardiac muscle have historically been difficult for unconjugated oligonucleotides to reach at pharmacologically useful levels. One emerging strategy is to attach the oligonucleotide to an antibody, antibody fragment, or peptide that binds a receptor such as transferrin receptor 1 (TfR1), which is expressed on muscle cells and undergoes internalization. Preclinical studies of TfR1-targeted antibody–oligonucleotide conjugates (AOCs) have demonstrated substantially greater oligonucleotide uptake and functional activity in skeletal and cardiac muscle than unconjugated molecules, and several programs have moved into late-stage clinical development.¹
The central nervous system presents a different barrier altogether. Approved neurological oligonucleotides such as nusinersen and tofersen bypass the blood-brain barrier through intrathecal administration, delivering drug directly into cerebrospinal fluid. Systemic delivery is considerably harder because most large or highly charged molecules cross the blood-brain barrier inefficiently. Researchers are therefore engineering antibody and other conjugate systems that engage endogenous transport pathways, including the transferrin receptor, to carry oligonucleotide payloads across the barrier.² These approaches have achieved broader brain exposure and parenchymal distribution in preclinical models, but these approaches remain at an early stage of clinical development.
The lung adds new variable: it can potentially be reached from either side. Systemic approaches must overcome biodistribution barriers that often favor the liver, while local administration through inhalation can place a nucleic-acid formulation directly into the respiratory tract. That creates its own engineering requirements, however. A formulation must survive aerosolization, navigate mucus and pulmonary clearance, and deliver its payload into the relevant epithelial or immune-cell population. Lipid and polymeric nanoparticles are among the approaches being explored for pulmonary nucleic-acid delivery, but performance can vary substantially with particle composition, aerodynamic properties and target cell type.
Immune cells pose yet another targeting problem. Rather than relying primarily on a ligand attached directly to an oligonucleotide strand, many programs are exploring lipid nanoparticles whose composition or surface ligands influence which immune-cell populations take up the payload. The challenge is achieving functional delivery into the intended cell type, such as a T cell, macrophage or dendritic cell, while limiting uptake elsewhere. Lipid composition, particle size, surface chemistry and targeting ligands can all alter that distribution.
The consequence of these different strategies is that delivery becomes an upstream decision with downstream effects across the entire program. The targeting strategy can influence biodistribution, dose and dosing frequency, safety margins, bioanalytical methods, formulation, impurity control, process development and manufacturing scale-up. Outside the liver, solving delivery is therefore not simply about getting an oligonucleotide into a new organ; it is about designing a development path around the biology and engineering constraints of that particular tissue.
Conjugation and Formulation Choices Shape the Downstream Analytical and Manufacturing Path
As oligonucleotide delivery becomes more sophisticated, the development work around the molecule expands with it. For conjugations, developers need processes that maintain the efficiency as scale increases, purification methods that separate the desired product from unconjugated or incompletely reacted species, and analytical methods capable of confirming identity, purity, sequence integrity and conjugate quality. Through its integrated CRDMO platform, WuXi TIDES supports oligonucleotide conjugates from discovery through development and commercial manufacturing, including oligonucleotide, peptide, linker, ligand, lipid and PEG chemistry within the same platform. For nanoparticle delivery, WuXi TIDES' LNP platform integrates lipid synthesis, formulation and process development, analytical support and sterile manufacturing.
That integration becomes consequential as oligonucleotide delivery moves beyond the liver. Extrahepatic programs are unlikely to converge on one universal technology; muscle, the central nervous system, lung and immune cells each require different solutions. For developers, the challenge is therefore not only to identify a delivery technology that works biologically, but to choose one that can also be characterized, manufactured and scaled reproducibly. In that sense, delivery strategy helps define the downstream development architecture of the medicine itself.
Frequently Asked Questions
Question: What makes oligonucleotide conjugates harder to manufacture?
Answer: Conjugation adds another layer of process and analytical complexity beyond oligonucleotide strand synthesis itself. Developers must control conjugation efficiency as the process scales, separate the desired conjugate from unconjugated or partially reacted species, and establish analytical methods that can characterize and release-test a multicomponent molecule including the oligonucleotide, linker, and targeting moiety as an integrated product.
Question: Why are purification and characterization important in oligonucleotide drug development?
Answer: Oligonucleotide synthesis can generate closely related impurities, including truncated or extended sequences and other process-related species, making purification and analytical characterization critical to product quality. Developers typically rely on techniques such as ion-exchange and reversed-phase chromatography, together with impurity profiling, forced-degradation studies, and ICH-compliant stability testing, to demonstrate that the intended product can be produced reproducibly and controlled throughout development. Keeping drug-substance and drug-product analytical strategies closely connected can also help maintain continuity in how impurities and degradation pathways are understood as the program advances.
Question: Why does continuity matter in oligonucleotide development from discovery to IND?
Answer: The path from discovery to IND can span synthesis, conjugation, formulation, analytical development, process development, and manufacturing, often on a compressed timeline. An integrated CRDMO model can keep these activities connected, allowing methods, process insights, and product understanding to carry forward as the molecule advances rather than being repeatedly transferred or rebuilt across multiple vendors.
¹ Malecova, Barbora et al. “Targeted tissue delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs).” Nucleic acids research vol. 51,12 (2023): 5901-5910. doi:10.1093/nar/gkad415.
² Scarlett J. Barker et al., Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier. Sci. Transl. Med. 16, eadi2245 (2024). DOI: 10.1126/scitranslmed.adi2245.
About WuXi AppTec
WuXi AppTec is a trusted partner and contributor to the pharmaceutical and life sciences industries, providing R&D and manufacturing services that help advance healthcare innovation. With operations across Asia, Europe, and North America, we offer integrated, end-to-end services through our unique CRDMO (Contract Research, Development, and Manufacturing Organization) platform. We are privileged to work alongside partners across 30+ countries, supporting their efforts to bring breakthrough treatments to patients. Guided by our vision that every drug can be made, and every disease can be treated, we are committed to advancing breakthroughs for patients—one collaboration at a time. Learn more at https://www.wuxiapptec.com.
