After years of progress in chemistry and delivery, oligonucleotide drugs are moving from rare diseases into cardiovascular, metabolic, neuromuscular, and central nervous system programs.
January 4, 2026
In 2025, oligonucleotide therapeutics moved further into the pharmaceutical mainstream. Publicly disclosed transactions across siRNA, antisense oligonucleotides (ASOs), microRNA programs, and delivery platforms totaled more than $27 billion by BiG's compilation of public data. Large pharmaceutical companies, including Novartis and Lilly, committed substantial capital to the field, while advances in multi-target design and extrahepatic delivery broadened the range of diseases that oligonucleotide medicines may be able to address.
The field is no longer defined only by rare genetic diseases. Cardiovascular disease, obesity, metabolic dysfunction, neuromuscular disorders, and diseases of the central nervous system are increasingly part of the development landscape.
1. What Are siRNA and Antisense Oligonucleotide Therapeutics?
The two most established oligonucleotide modalities are antisense oligonucleotides and small interfering RNA. Both act at the RNA level, but they use different mechanisms.
Antisense oligonucleotides (ASOs)
ASOs are short, synthetic single-stranded nucleic-acid sequences designed to bind a specific RNA target. Depending on their chemistry and design, they can recruit cellular enzymes that degrade the target RNA, block translation, or alter RNA splicing. This flexibility has made ASOs useful across several genetic and neurologic diseases.
Small interfering RNA (siRNA)
siRNA molecules are double-stranded RNA constructs that engage the RNA-induced silencing complex (RISC). One strand guides RISC to a complementary messenger RNA, which is then cleaved and degraded. The result is sequence-specific gene silencing.
For both modalities, development has historically been constrained by two challenges: stability in the body and efficient delivery to the intended tissue. Chemical modifications and delivery systems have progressively reduced these barriers, supporting commercial products in diseases such as hereditary transthyretin amyloidosis and hypercholesterolemia.
2. Why Oligonucleotide Therapeutics Attracted More Deal Activity
By 2025, the combination of validated mechanisms, approved products, and improved delivery technologies had made oligonucleotide platforms increasingly attractive to pharmaceutical companies. BiG's review of publicly announced transactions identified more than $27 billion in disclosed deal value across siRNA, ASO, microRNA, and related technologies.
Novartis was one of the most active participants. In October 2025, it agreed to acquire Avidity Biosciences for approximately $12 billion, adding Avidity's antibody-oligonucleotide conjugate platform and late-stage neuromuscular programs; the transaction was completed in February 2026. Novartis also completed its acquisition of Regulus Therapeutics, whose lead program farabursen targets miR-17 in autosomal dominant polycystic kidney disease. In September 2025, Novartis entered a global collaboration with Arrowhead Pharmaceuticals for ARO-SNCA, a preclinical siRNA program targeting alpha-synuclein, plus additional targets using Arrowhead's TRiM platform.
Lilly also expanded its activity in metabolic and oligonucleotide drug discovery through multiple partnerships during 2025. Other large pharmaceutical companies, including Sanofi, Biogen, and Novo Nordisk, continued to evaluate or acquire oligonucleotide assets and delivery technologies.
Several China-based oligonucleotide companies also expanded international collaborations during this period. Rather than treating these transactions as a separate regional story, they are better understood as part of the broader globalization of oligonucleotide discovery and platform licensing.
3. The Delivery Platforms Expanding siRNA Beyond the Liver
GalNAc established the liver as the first scalable delivery destination
Alnylam's development of GalNAc-conjugated siRNA demonstrated that highly efficient and selective liver delivery could be achieved through receptor-mediated uptake. That advance helped turn the liver into the first broadly validated organ for subcutaneously delivered siRNA therapeutics.
Alnylam's commercial portfolio has expanded since the 2018 approval of Onpattro, including products such as Givlaari for acute hepatic porphyria and Oxlumo for primary hyperoxaluria type 1. Inclisiran (Leqvio), developed by The Medicines Company and now commercialized by Novartis, targets PCSK9 to lower LDL cholesterol. After the initial and three-month doses, it is administered every six months, illustrating the potential of infrequent dosing in a large chronic-disease market.
Extrahepatic delivery is the next major engineering problem
The next phase of the field depends heavily on moving beyond hepatocytes. Arrowhead's Targeted RNAi Molecule (TRiM) platform uses modular targeting ligands to direct RNAi triggers toward selected tissues or cell types. The company has been developing approaches for central nervous system delivery, including programs designed around receptors such as transferrin receptor 1, as well as metabolic targets outside conventional liver programs.
Avidity's antibody-oligonucleotide conjugate platform uses antibody-mediated targeting to deliver oligonucleotide payloads to muscle and other tissues. The platform's ability to reach tissues that have been difficult for conventional oligonucleotide approaches was a central rationale for Novartis' acquisition.
4. Examples of Emerging Global Oligonucleotide Pipelines
Beyond the largest U.S. and European developers, a broader group of companies is building differentiated pipelines around target selection and delivery.
Argo Biopharma has built an RNAi platform and a pipeline spanning cardiovascular and other diseases, and has entered multiple collaborations with Novartis. Ribo Life Science has advanced RBD4059, an siRNA targeting factor XI, as an anticoagulation strategy while also developing extrahepatic delivery platforms. SanegeneBio has focused on obesity, cardiometabolic disease, and autoimmune indications, including programs that target INHBE and delivery technologies intended for adipose and muscle tissue.
Yuekang Pharmaceutical has also advanced long-acting liver-targeted siRNA programs, including candidates directed at hepatitis B, PCSK9, and angiotensinogen. These programs illustrate a broader trend: oligonucleotide development is becoming less concentrated in a small number of specialist companies and increasingly distributed across global biotech ecosystems.
5. Four Trends Shaping the Next Phase of Oligonucleotide Drug Development
Multi-target RNAi strategies
Most first-generation oligonucleotide medicines are designed against a single sequence or gene. In diseases driven by multiple pathways, developers are increasingly exploring dual-target RNAi constructs. The rationale is similar to combination therapy: coordinated modulation of two disease drivers may produce broader or more durable benefit than either alone. Whether these designs can consistently deliver superior clinical outcomes remains to be established.
Extrahepatic delivery
Delivery remains one of the field's most important competitive boundaries. GalNAc solved a major liver-targeting problem, but muscle, adipose tissue, the central nervous system, and other organs require different transport and uptake strategies. Antibody-oligonucleotide conjugates, receptor-targeted ligands, and other targeted delivery systems are therefore becoming central platform assets.
Combination approaches with metabolic therapies
Oligonucleotide drugs are also being tested conceptually and preclinically in combination with established metabolic therapies. In 2025, Arrowhead reported preclinical work combining an ALK7-targeted siRNA approach with tirzepatide, with the goal of improving weight loss while preserving lean mass and extending metabolic control. These findings remain preclinical, but they illustrate how RNAi may be used as a complementary mechanism rather than only as a stand-alone therapy.
Expansion from rare disease to large chronic markets
Early oligonucleotide products benefited from the clearer development pathways and concentrated patient populations associated with rare diseases. As delivery and safety experience expand, the field is moving toward much larger populations in cardiovascular, metabolic, and neurologic disease. Inclisiran is one important example of this transition, and the growing number of CNS and metabolic collaborations suggests that developers expect the addressable market to broaden further.
What Comes Next for Oligonucleotide Therapeutics?
The recent growth of oligonucleotide therapeutics is not the result of a single breakthrough. It reflects the combination of better chemistry, validated mechanisms, more mature delivery systems, clinical proof of concept, and sustained investment.
The next phase will depend less on whether RNA can be drugged and more on where it can be delivered, how durably and selectively targets can be modulated, and whether complex designs such as multi-target constructs or extrahepatic delivery platforms can show meaningful clinical advantages.
Why This Matters
For drug-discovery teams, the most important change is the expansion of the oligonucleotide design space. siRNA and ASO platforms are increasingly being evaluated not only for rare genetic diseases, but also for major chronic diseases and tissues that historically were difficult to reach. Delivery—not target biology alone—will continue to shape which programs are clinically and commercially viable.
References
• BiG source references: China Merchants Securities research; Haitong International research; Guojin Securities research; company websites and public disclosures.
• Novartis. Agreement to acquire Avidity Biosciences, October 26, 2025; acquisition completed February 27, 2026.
• Novartis. Acquisition of Regulus Therapeutics announced April 30, 2025; completed June 25, 2025.
• Arrowhead Pharmaceuticals. Global license and collaboration agreement with Novartis for ARO-SNCA, September 2, 2025; closed October 2025.
• U.S. Food and Drug Administration. Leqvio (inclisiran) dosing and approval information.
Reprinted from BiG. BiG Bio Innovation Society is a nonprofit life-science industry platform connecting researchers, companies, investors, and innovators, and is an affiliated association of Direct2Lab.
