How China Built Its Oligonucleotide Drugs Industry

China’s oligonucleotide drugs industry grew from a near-empty field in the 1980s into a pipeline of about 100 clinical-stage programs today. No single breakthrough explains that shift. Three generations of academic researchers built the chemistry, the delivery science, and the industry links over four decades.

Why this niche stayed cold for so long

Twenty years ago, RNA interference was still a frontier concept inside overseas laboratories, and almost no one in Chinese universities could read its clinical value. There were no mature nucleic acid chemistry courses, no systematic delivery research, and no academic ecosystem that connected teaching, research, and industry.

The science moved fast elsewhere. In 1998 the first antisense oligonucleotide drug reached the market, and the same year the RNA interference mechanism was described. Those two events opened the modern oligonucleotide field. Yet in China the people who could work at that frontier were very few. When the broader gene therapy field hit a severe safety crisis around 2000, with fatal adverse events in early trials, many researchers worldwide moved to small molecules and antibodies to avoid the risk. Only a small group stayed in nucleic acids.

That context matters because it explains the starting line. An oligonucleotide drug is a short, designed strand of nucleic acid that changes how a cell reads a gene. The family now covers antisense oligonucleotides, small interfering RNA, and aptamers. Building it requires two hard sciences at once: nucleic acid chemistry to make a stable, specific strand, and a delivery system to get that strand into the right cells without poisoning the patient.

The first generation built the chemistry base

The earliest Chinese work on nucleic acid chemistry came out of a pharmacology school in Beijing in the 1980s. A senior medicinal chemist there turned a small testing building into the country’s first nucleic acid research group, working at a time when there were no drawing programs and every chemical structure had to be sketched by hand with a ruler and a steel plate.

By the late 1980s the group had started systematic nucleic acid research. In 1997 one of its leaders published the first authoritative Chinese book on drugs that target nucleic acids, covering computer aided drug design, antisense chemistry, sequence specificity, and nucleic acid conformation decades before the local field was ready for it. The group trained more than 110 researchers over the following decades, and its head made a point of passing student slots to younger returnees from overseas so the field would branch out rather than concentrate in one lab.

That move paid off later. The first generation never produced a blockbuster, but it produced a method, a textbook, and a network of people who could teach the next generation.

The second generation bridged lab and industry

The real industry takeoff came after RNA interference won the Nobel Prize in 2006. That award sent global capital into the field, and in the same year one of the early returnees founded a small nucleic acid company in the Yangtze River delta. By 2007 a small nucleic acid research institute had formed in the Kunshan area with public funding for several research groups, and the region began to gather the country’s nucleic acid talent.

The years 2010 to 2012 were the recognized low point for small interfering RNA. After a wave of investment, confidence collapsed when delivery problems caused repeated clinical failures, including serious safety issues and patient deaths. Multinational companies shut down or sold their oligonucleotide units. The cold did not drive the Chinese researchers away. It pushed a batch of them to start companies and fill the gaps in the local supply chain.

Two technical threads defined this generation. One researcher in Beijing built a composite nanoparticle delivery system that anchors the drug with hydrogen bonds and pi stacking from nucleoside lipids, plus electrostatic binding from a cysteine based cationic lipid. This design cuts the cationic carrier load to about one fifth of a standard lipid nanoparticle, improves safety, and can be tuned to reach organs beyond the liver. It carries antisense, small interfering RNA, messenger RNA, and aptamers through several routes of administration.

A researcher at a Nanjing university took a different path: an endogenous delivery system that uses the human liver as a bioreactor to make precursor small RNA, process it into mature small interfering RNA, package it in extracellular vesicles, and send it through the blood and lymph to many organs. This inside out approach avoids the narrow liver only focus of most commercial delivery and opens a route to rare diseases outside the liver.

The third generation pushes the frontier

After 2015, as capital returned, a cohort of researchers born in the 1980s took the front line of original chemistry. One at Nanjing University focused on threose nucleic acid, a non natural backbone where the natural ribose is replaced with a four carbon sugar. This rebuilds the whole molecular logic and improves stability in the body, while also speaking to basic questions about the origin of life.

The same university produced a partner who works downstream: microRNA biology, clinical translation, and in vitro diagnostic development. A third researcher returned to the Beijing pharmacology school in 2021 to keep the academic line alive. Mentoring in this generation often happened at specialist conferences, where senior figures helped younger ones reframe dense chemistry for drug developers and pointed them toward industry applications.

Where the pipelines stand now

The field has moved from papers to products. About 100 domestic oligonucleotide programs are now progressing through clinical stages. On the capital side, one company listed in Hong Kong at the end of 2021 as an early nucleic acid drug issuer, and another completed a Hong Kong listing in January 2026 that raised more than 1.8 billion HKD, the largest such initial public offering in the global field by proceeds.

Several programs have reached phase III. A PCSK9 small interfering RNA from a major domestic pharma group is the first homegrown candidate of its kind to enter phase III. An antisense oligonucleotide aimed at a functional cure for hepatitis B has finished phase III patient enrollment. Additional small interfering RNA and antisense candidates from other domestic developers are also in phase III, moving the field from clinical validation toward launch.

Three generations carried the China oligonucleotide drug industry forward

Generation	Period	Core contribution	Signature work
First	1980s to 2000	Nucleic acid chemistry base and talent pipeline	First Chinese textbook on nucleic acid targeted drugs
Second	2006 to 2014	Lab to industry bridge and delivery science	Composite nanoparticle delivery and endogenous vesicle delivery
Third	2015 to now	Frontier backbone chemistry and translation	Threose nucleic acid and microRNA diagnostics

Delivery platforms compared

Platform	Anchor mechanism	Strength	Limit
Standard lipid nanoparticle	Electrostatic binding of cationic lipid to nucleic acid	Proven, liver focused	High carrier dose, immune and organ toxicity
GalNAc conjugate	Receptor mediated uptake in liver	Simple, potent for hepatocytes	Liver only
Composite nanoparticle (NLNP)	Hydrogen bond and pi stacking plus light electrostatic binding	One fifth cationic load, multi organ tuning	Newer, less validated at scale
Endogenous vesicle system	Body makes and packages the strand	Avoids synthetic packaging, broad reach	Depends on native biology

Milestone timeline

Year	Event
1997	First authoritative Chinese book on nucleic acid targeted drugs published
1998	First antisense oligonucleotide approved globally; RNA interference described
2006	RNA interference wins Nobel Prize; first domestic company founded
2008	Regional small nucleic acid research institute established
2010 to 2012	Small interfering RNA downturn after delivery failures
2014	GalNAc targeted delivery breaks through
2021	One nucleic acid company lists in Hong Kong
2026	Another completes a large Hong Kong listing

Representative clinical stage programs

Program	Target or indication	Sponsor	Stage
PCSK9 small interfering RNA	Cholesterol control	Major domestic pharma group	Phase III
Antisense oligonucleotide	Hepatitis B functional cure	Domestic biotech	Phase III enrollment complete
Small interfering RNA	Lipid and metabolic	Domestic oligonucleotide company	Phase III
Small interfering RNA	Hepatitis B	Major domestic pharma group	Phase III

What actually built the track

A hero paper or a patented invention makes a clean story, but the track was built in ordinary work that never made it into a paper: lab discussions repeated until they stuck, frank exchanges at industry dinners, and years of cross campus collaboration. A cold niche turned into a busy field because three generations kept sharing methods, students, and problems instead of guarding them.

The pattern holds well beyond this one field. Deep tech rarely rises on a single discovery. It rises when the people who hold the early knowledge teach the next cohort, link the lab to the factory, and stay in the room through the downturns.

Practical takeaways

• Build the chemistry base before the delivery hype. A drug strand that is unstable or non specific cannot be saved by a fancy carrier.
• Treat delivery as the real bottleneck. Most of the 2010 to 2012 failures were delivery problems, not target problems.
• Spread the talent, do not hoard it. Passing student slots and methods to newcomers multiplies the field faster than one strong lab.
• Use the downturn to go vertical. The cold years are when local supply chain gaps get filled by new companies.
• Keep academic and industry links alive through repeated, specific exchange, not one off meetings.

Limitations

This is a historical and industrial overview rather than a clinical review. Reported clinical stages change quickly, and readers should confirm current trial status from primary registries before relying on any program listed here. Company names and milestone dates are included as public industry facts and may shift. The chemistry and delivery concepts described are established, but specific performance claims for any one platform should be read against the originating publications.

Bottom line

China’s oligonucleotide drug industry did not appear because a niche suddenly got hot. It appeared because a first generation planted the chemistry, a second generation built the delivery and the companies, and a third generation is now extending the backbone itself. About 100 clinical programs and several phase III candidates are the visible result. The part you cannot see in the numbers is a habit of teaching the next cohort instead of competing with it.

FAQ

What are oligonucleotide drugs?

Oligonucleotide drugs are short, designed strands of nucleic acid that change how a cell reads a gene. The family includes antisense oligonucleotides, small interfering RNA, and aptamers. They work inside the cell to block, degrade, or redirect a disease causing message rather than occupying a protein from the outside like a small molecule. This makes them useful for targets that ordinary drugs cannot reach.

When did RNA interference win the Nobel Prize?

RNA interference won the Nobel Prize in Physiology or Medicine in 2006, shared by the two researchers who explained the mechanism. That award pushed global capital and talent into the small nucleic acid field and helped trigger the first wave of domestic companies in China. It also set off a long delivery struggle, because the science was clear years before safe and effective carriers existed.

What caused the 2010 to 2012 siRNA downturn?

The small interfering RNA field collapsed between 2010 and 2012 after a wave of investment met repeated clinical failures caused by delivery problems. Candidates showed weak efficacy or serious safety issues, and some trials reported patient deaths. Multinational companies shut down or sold their oligonucleotide units. The crisis was about carriers, not targets, and it pushed researchers toward better delivery rather than new sequences.

What is GalNAc delivery and why did it matter?

GalNAc delivery is a conjugate that binds a sugar on the surface of liver cells, pulling the attached oligonucleotide into hepatocytes with high efficiency. It broke through around 2014 and rescued the field because it made liver targeted small interfering RNA simple and potent. Its limit is that it reaches the liver almost exclusively, so it does not help diseases outside the liver.

How does the NLNP delivery system differ from standard LNP?

The composite nanoparticle system, often called NLNP, anchors the drug with hydrogen bonds and pi stacking from nucleoside lipids plus light electrostatic binding, instead of relying mainly on cationic lipids. This cuts the cationic carrier load to about one fifth of a standard lipid nanoparticle and reduces immune and organ toxicity. It can also be tuned to reach organs beyond the liver, where most commercial carriers still fail.

What is threose nucleic acid, or TNA?

Threose nucleic acid, or TNA, is a non natural genetic system that replaces the natural ribose sugar with a four carbon threose. This rebuilds the molecular recognition logic of the strand and improves its stability in the body. It also speaks to basic origins of life questions. A Nanjing University researcher made it the focus of a small but original Chinese line of backbone chemistry in the 2010s.

What is extracellular RNA self delivery?

Extracellular RNA self delivery is an endogenous approach in which the body makes and packages the therapeutic strand itself. The liver acts as a bioreactor that produces precursor small RNA, processes it into mature small interfering RNA, and wraps it in extracellular vesicles that travel through blood and lymph to many organs. It avoids synthetic packaging and escapes the liver only limit of most commercial routes.

How many Chinese oligonucleotide drugs are in clinical trials?

By the mid 2020s, about 100 domestic oligonucleotide programs were progressing through clinical stages. The count spans antisense oligonucleotides, small interfering RNA, and related modalities from both large pharma groups and dedicated oligonucleotide companies. The number moves quickly, so readers should check current trial registries for an exact figure before citing it.

Which Chinese siRNA drugs have reached phase III?

Several homegrown small interfering RNA candidates have reached phase III. A PCSK9 siRNA from a major domestic pharma group was the first of its kind locally to enter phase III for cholesterol control. A hepatitis B antisense oligonucleotide has finished phase III enrollment, and additional domestic small interfering RNA and antisense programs are also in phase III across metabolic and viral indications.

What is the difference between siRNA and antisense oligonucleotides?

Antisense oligonucleotides bind a target messenger RNA and block its use or flag it for destruction through a specific enzyme. Small interfering RNA enters the silencing complex and triggers degradation of the matched message. Both are oligonucleotides, but they act at different steps and use different cellular machinery. Small interfering RNA is usually shorter and leans on delivery conjugates or particles.

Why did China’s nucleic acid field start so late?

China’s nucleic acid field started late because there were almost no courses, no delivery research, and no industry ecosystem for it in the 1980s and 1990s. Even after RNA interference appeared in 1998, only a few people could read its clinical value. A gene therapy safety crisis around 2000 pushed many researchers toward small molecules and antibodies, leaving a small group to hold the line until capital returned.

What does the future hold for China’s oligonucleotide industry?

The future rests on moving several phase III programs to approval, proving delivery beyond the liver, and turning backbone chemistry like threose nucleic acid into drugs. Capital is active, with large listings and outbound licensing deals. The open risk is that delivery and stability still gate most targets, so the next gains will come from carriers and chemistry, not from more sequences aimed at the same organs.