Rethinking the Oligonucleotide Journey

Why integration matters

As oligonucleotide therapies expand from rare neurological disorders to broader cardiometabolic diseases, advances in molecular design and delivery are creating new therapeutic possibilities. Translating these advances into viable treatments requires integrated expertise across research, development, and manufacturing. In a recent article published in Pharmaceutical Outsourcing, Dr. Sajesh Parathath, Executive Director within the biology division at WuXi AppTec, explores molecular design optimization, advances in extrahepatic delivery, and integrated development strategies, offering insights into the evolving challenges and opportunities in oligonucleotide drug development.

Over the past decade, oligonucleotide therapies have progressed from early scientific exploration into a more established therapeutic modality. Their central appeal lies in their unique ability to intervene at the transcript level, allowing them either to repress disease-causing proteins or to engineer outcomes that restore pathways that improve the disease state. While small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) remain the foundational vehicles driving this field, the modern toolkit includes additional mechanisms and approaches such as splice-switching oligonucleotides (SSOs), RNA activation (saRNA), MicroRNA modulators, and RNA aptamers. The therapeutic reach of these modalities can span a broad spectrum of diseases, from rare neurological disorders to more common conditions such as cardiometabolic diseases.

Although advances in chemistry and delivery technologies fuel much of this clinical progress, generating promising laboratory biology is only the initial step. As the underlying science becomes more sophisticated, the greater challenge often lies in assembling the technical, translational, manufacturing, and development capabilities required to convert that science into a viable therapeutic program. Consequently, integrated strategic partnerships play an increasingly critical role for companies navigating the steep execution risks of the oligonucleotide landscape.

The Evolution of Oligonucleotides: Improving Drug-Like Properties and Targeted Delivery

The maturation of oligonucleotide therapies has depended on solving two fundamental challenges: improving their drug-like properties, including metabolic stability, and delivering them to the right tissues and cells.

RNA and DNA-like molecules are not naturally optimized to behave as drugs. Unmodified siRNAs and ASOs are susceptible to nuclease degradation. They are large, highly charged, and often unable to cross cell membranes efficiently. For siRNA in particular, endosomal escape remains one of the most important rate-limiting steps, especially when delivery moves beyond the liver.

To improve the drug-like properties of oligonucleotides, chemistry has become inseparable from the biology of oligonucleotide medicines. For siRNAs, chemical stabilization has evolved from minimal modification to extensive modification. Common strategies include 2’-O-methyl (2’OMe) and 2’-deoxy-2’-fluoro (2’F) ribose modifications, phosphorothioate (PS) backbone modifications, and 5’-(E)-vinyl phosphonate (5’(E)-VP) designs. The 2’-OMe and 2’F modifications can increase potency and reduce immune activation without interfering with RNA-induced silencing complex (RISC) loading, while the presence of 5’(E)-VP increased siRNA stability and potency, and PS modifications at the ends of duplex siRNAs help protect against exonucleases.

The design of ASOs has also progressed through multiple generations. Naturally occurring ASOs are labile and have lower tissue and cellular uptake, which led to the use of PS backbone modification in first-generation ASOs. This modification increases lipophilicity, supports binding to serum proteins, and helps reduce rapid kidney clearance. Second-generation ASOs added 2’-O-methoxyethyl modifications to the ribose in combination with the PS backbone. This chemistry rigidifies the overall structure, increases affinity for target RNA, hinders nuclease attack, decreases nonspecific interactions, and can extend tissue half-life. Other designs, including phosphorodiamidate morpholino oligonucleotides (PMOs) and thiomorpholino oligonucleotides (TMOs), can function as steric blockers for exon skipping, an approach that is especially relevant in Duchenne muscular dystrophy (DMD).

The second major challenge for developing oligonucleotide therapeutics was targeted delivery. The liver provided the first major clinical proving ground for oligonucleotide delivery. Two delivery systems have been especially important: lipid nanoparticles (LNPs) and trivalent N-acetylgalactosamine, or GalNAc, conjugation. The first approved siRNA medicine used LNPs, while most subsequently approved siRNA drugs have used GalNAc conjugation for hepatocyte delivery.

Liver-targeted delivery provided important commercial and clinical proof-of-concept. However, the next frontier is expanding the reach of oligonucleotides to extrahepatic tissues. To extend LNP delivery beyond the liver, researchers are exploring strategies to target LNPs from hepatic uptake and retarget them to selected tissues. These strategies include changes in particle size, surface charge, lipid composition, administration route, surface ligands, and selective organ targeting approaches.

Conjugation-based delivery is becoming one of the most important strategies for extrahepatic oligonucleotide therapeutics. Antibody–oligonucleotide conjugates (AOCs) combine the targeting specificity of monoclonal antibodies with the sequence-specific activity of siRNAs or ASOs. This approach is particularly valuable for organs that are difficult to reach through conventional systemic delivery. For central nervous system delivery, transferrin receptor 1 has emerged as an important target because it is abundantly expressed on brain endothelial cells and can support transport across the blood–brain barrier. However, AOC design requires careful optimization of antibody format, linker, conjugation chemistry, oligonucleotide-to-antibody ratio/DAR, receptor affinity, and pharmacokinetic properties to achieve a favorable therapeutic index.

In parallel, the neuromuscular field further illustrates how different delivery architectures can be adapted to the same biological objective. Enhanced delivery oligonucleotide peptide platforms are being used to improve nuclear delivery of PMOs for exon skipping in DMD. Peptide–PMO conjugates have shown improved exon skipping and dystrophin production in DMD models. Other platforms use antibody fragments, cleavable linkers, and oligonucleotide cargos to direct exon-skipping therapeutics toward skeletal and cardiac muscle.

Lipids offer another route to extrahepatic delivery. By conjugating siRNAs or ASOs to lipids with different levels of hydrophobicity, researchers can influence serum protein binding, tissue distribution, renal clearance, and cellular uptake. Studies have shown that, after systemic administration, siRNAs conjugated to more hydrophobic lipids, such as cholesterol, tend to distribute preferentially to the liver. By contrast, siRNAs conjugated to less hydrophobic lipids, such as docosahexaenoic acid (DHA), show a greater tendency to accumulate in the kidney.

Together, these examples show that extrahepatic delivery is not defined by a single technology. Rather, it represents a complex design space in which antibody format, peptide sequence, lipid type, linker chemistry, cargo selection, and dosing strategy all influence the final pharmacological outcome.

While systemic delivery represents a major route for the development of oligonucleotide therapeutics, local delivery remains important. Intrathecal and intracerebroventricular routes can deliver ASOs to the central nervous system. Intravitreal administration can be used for ocular indications. Inhalation may support pulmonary delivery. These routes avoid some systemic barriers, but they also introduce their own constraints, including distribution within the target organ, durability, tolerability, and patient convenience. The future of extrahepatic delivery will likely involve both systemic and local approaches, selected according to disease biology, target tissue, therapeutic window, and desired duration of action.

The central nervous system, muscle, eye, lungs, and immune system are emerging as key frontiers for the next wave of oligonucleotide delivery. Progress in these areas will require more than making oligonucleotides more stable or attaching them to new ligands. It will require matching molecular design with tissue biology. Developers must determine which oligo tool is better suited to a target based partly on where the relevant RNA is located. ASOs may be advantageous for nuclear targets and splice modulation, while siRNAs may offer durable cytoplasmic mRNA silencing. Delivery vehicles must be evaluated not only for target binding, but also for receptor availability, trafficking, endosomal escape, pharmacokinetics, biodistribution, and toxicology.

As these technologies grow in complexity, they are also eliminating the traditional boundaries between scientific disciplines. In parallel, they are broadening the range of addressable diseases toward more prevalent conditions, including those with complex and multifactorial disease biology. Maximizing their potential now requires highly integrated development frameworks that harmonize chemistry, structural biology, translational modeling, and development strategy from the beginning.

The Convergence of Chemistry and Biology Is Redefining Drug Development

For decades, drug development was often organized into relatively distinct disciplines. Chemists optimized molecules. Biologists evaluated function. Manufacturing teams scaled production. Each group operated within well-defined boundaries. Today, that model is rapidly changing.

As modern modalities become more sophisticated, development teams must navigate increasingly complex steps, technologies, and chemistries. During the discovery phase, for example, researchers need integrated capabilities that span from sequence design through functional validation. These capabilities are critical to improving development efficiency and increasing the likelihood of success. Teams also need access to high-fidelity translational models that can generate the high-quality data required for informed decision-making.

Beyond discovery, developers face growing complexity in manufacturing and analytics as these novel modalities advance through development. For example, sourcing chemically modified nucleotides and unnatural amino acids for peptide-conjugated oligonucleotides can become a bottleneck when advancing a preclinical candidate into the clinic. Moreover, unlike traditional small molecules, oligonucleotides—particularly GalNAc-conjugated siRNAs—undergo complex nuclease-mediated metabolism that can vary significantly across biological compartments. These differences may also result in distinct toxicology profiles, making conventional in vitro systems insufficient for translational prediction.

As a result, the traditional boundaries separating disciplines are becoming increasingly blurred.

This is why integrated development is becoming increasingly important for complex modalities. A change that improves potency or tissue uptake may also affect chemistry, manufacturing, and controls (CMC) complexity. Similarly, a delivery technology that performs well in an early biological model may create new challenges in scale-up, characterization, release testing, or toxicology interpretation. These issues are difficult to solve in isolation because each decision can affect the next stage of development.

From discovery to toxicology and development, and from biology to chemistry and strategy, no single individual can possess expertise across the entire process. To reduce friction during handoffs, it is increasingly valuable to bring experts together from the outset to design the best possible development plan, rather than switching teams at each stage. In complex drug development, including oligonucleotide programs, teams that can evaluate therapeutic candidates through both scientific and operational lenses are increasingly needed.

By bringing these capabilities together early, developers can look beyond the immediate next milestone and anticipate challenges three or four stages ahead. That is the true value of an integrated model—and what can make a meaningful difference in the success of drug development.

A Strategic Advantage for Biotech Companies

This trend extends well beyond oligonucleotides. From nanoparticles and antibody-drug conjugates (ADCs) to degraders and other emerging modalities, each technology brings its own manufacturing, analytical, and development complexities. Success now requires teams with experience across a broad range of platforms, as well as the adaptability to navigate modalities that may not yet exist today.

For resource-constrained biotech companies, building this breadth of expertise internally is often not realistic. When funding cycles are longer and budgets are tighter, companies are often forced to make difficult choices. Many organizations enter development with multiple promising assets, only to narrow their focus to a single lead candidate as resources become strained.

As a result, many innovators are seeking partners with integrated development capabilities. They want partners who understand the broader context of the program, proactively solve problems, evaluate alternative paths, and help guide key decisions along the way.

For emerging biotech companies with unique biological insights or technical innovations, this type of partnership can be especially valuable. It allows innovators to remain focused on their core scientific strengths while leveraging external expertise in development, manufacturing, and regulatory strategy. These partners can apply lessons learned across multiple programs to guide molecule selection, delivery strategies, and development planning from the outset, helping developers anticipate challenges long before they emerge.

Looking Ahead

The history of oligonucleotide therapeutics illustrates that transformative medical progress occurs when foundational scientific breakthroughs are matched by equally robust advances in development infrastructure. Over the next decade, oligonucleotides are poised to expand their clinical footprint beyond reactive treatment and toward proactive preventive intervention for highly prevalent chronic conditions.

Continued progress in extrahepatic delivery will unlock reliable, targeted access to the central nervous system, skeletal and cardiac muscle, and other historically restricted tissues. In some cases, these advanced platforms can virtually eliminate traditional patient compliance barriers by only needing one to two administrations of the drug per year. Furthermore, oligonucleotides may be able to engage multiple targets with a single molecule/dose, potentially enabling the treatment of multiple diseases through an integrated therapeutic approach.

Realizing this paradigm shift requires more than designing better molecules. It demands the architecture of highly integrated systems, a framework that seamlessly connects early-stage discovery, translational biology, scalable manufacturing, and commercial execution. Ultimately, the next frontier of medicine will not be defined by isolated laboratory breakthroughs, but by our collective ability to achieve full operational integration, turning scientific possibility into scalable, sustainable patient impact.