For decades, drug development has chased the promise of treating disease at its genetic origins rather than managing symptoms downstream. Gene replacement therapies and genome-editing tools like CRISPR have shown that such interventions are possible, but they also carry significant complexity. Delivery challenges, immune responses, high manufacturing costs, and uncertainty around long-term safety have slowed the path from scientific excitement to widespread clinical adoption.
In parallel, another form of gene therapy has been steadily advancing — one that does not alter DNA at all. Small interfering RNA (siRNA) therapies silence harmful genes temporarily, using a natural regulatory process known as RNA interference (RNAi). Instead of changing the genome, siRNA blocks the messenger RNA (mRNA) that directs protein production. Its effects are strong, but reversible: stop dosing, and gene expression returns to baseline.
This combination of precision, durability, and reversibility has made siRNA increasingly attractive to pharmaceutical companies looking for therapeutic tools suited not just to rare diseases, but to large chronic markets. Since the approval of patisiran in 2018, seven total siRNA medicines have reached the market, all of them treating diseases driven by well-characterized genetic mechanisms in the liver. Their success is changing the conversation within the industry and leading companies like Novartis, GlaxoSmithKline (GSK), Novo Nordisk, AbbVie, and Sarepta Therapeutics to make targeted acquisitions, partnerships, or pipeline pivots to build RNAi capabilities.
What makes siRNA therapies different?
What sets siRNA therapies apart is not just what they target, but where in the biological process they act. Traditional small-molecule drugs and antibodies focus on proteins; however, only about 1.5 percent of the human genome encodes proteins, and roughly 80 percent of those are considered “undruggable” with conventional approaches.
In contrast, siRNA operates upstream, at the level of nucleic acids. By binding to mRNA, these therapies prevent disease-driving proteins from ever being produced. Unlike traditional drugs, which rely on complex three-dimensional protein structures, nucleic acid therapies are theoretically applicable to virtually any genetic target. Once the sequence of a disease-causing gene is known, designing a therapy that binds to it is relatively straightforward. The simplicity of nucleotide synthesis and relatively low cost further accelerate research and development, making nucleic acid drugs accessible to a broader range of therapeutic targets.
This design logic makes siRNA fundamentally programmable. A therapy can be built directly from genomic information, accelerating early research and manufacturing. Synthesizing short stretches of RNA is far more standardized and modular than producing complex protein biologics. That means once a delivery platform is established, new siRNA drug candidates can move into development faster — and with higher confidence that they will behave predictably.
As Jianbo Diao, a bioanalysis scientist at Wuxi AppTec, told DDN, “Once a delivery system is optimized, it can be readily adapted for different gene targets by simply altering the guide strand sequence. This modularity supports pipeline efficiency and opens the door to rapid candidate generation within a single chemical framework.”
Additionally, because the silencing effect is mediated through the cell’s own RNA interference machinery, the impact of siRNAs can be both potent and long-lasting. Many siRNA therapies in development are dosed only a few times per year — a meaningful shift for chronic conditions where daily pills or weekly injections can erode adherence over time.
From concept to delivery
Despite these advantages, the path from conceptual siRNA therapy to FDA-approved drugs has been far from straightforward. In its native form, siRNA faces formidable biological hurdles. It is fragile, quickly degraded by enzymes in the bloodstream, and its size and negative charge prevent it from easily crossing cell membranes. Additionally, unmodified siRNAs can inadvertently trigger the immune system or silence unintended genes.
"For years, siRNA was a beautiful idea with a practical problem: You could silence a disease-causing gene in a dish, but you couldn’t get the drug into the right cells in a living person without it getting destroyed. The turning point was showing durable target knockdown and real clinical benefit in humans, first in the liver,” William Soliman, the founder and CEO of the Accreditation Council for Medical Affairs (ACMA), told DDN.
That’s the biotech equivalent of landing on the moon. After that, investors and pharma stopped calling it speculative science and started calling it a drug modality.
- William Soliman, Accreditation Council for Medical Affairs
The breakthroughs that unlocked clinical success were largely centered on chemical modification and targeted delivery. Alnylam Pharmaceuticals pioneered RNAi therapeutics with Enhanced Stabilization Chemistry, raising the resilience of siRNA molecules in circulation, while its N-acetylgalactosamine (GalNAc) conjugate platform enabled highly specific delivery to liver cells. By attaching GalNAc ligands to the siRNA, the therapeutics are taken up primarily by hepatocytes. This targeted approach not only improves the efficacy of the therapy but also reduces off-target effects and potential toxicity.
These innovations opened the door to the first generation of FDA-approved siRNA therapies for hereditary amyloidosis, acute hepatic porphyria, primary hyperoxaluria, and elevated low-density lipoprotein cholesterol.
"These were first-in-class RNAi drugs that demonstrated meaningful outcomes in rare, severe diseases,” noted Soliman. “That’s the biotech equivalent of landing on the moon. After that, investors and pharma stopped calling it speculative science and started calling it a drug modality.”
Moving beyond the liver
The first wave of siRNA medicines proved that gene silencing could be safe, precise, and clinically meaningful — but all of those therapies work in the liver. The next chapter is about reaching the tissues outside the liver.
"Getting beyond the liver is what's hard. Hepatocytes are easy because they naturally clear things from the bloodstream and [Alnylam’s] GalNAc exploits that. Getting efficient, specific delivery to heart, lung, kidney, muscle, tumors, or the [central nervous system] without triggering immune toxicity is still the big technical barrier,” said Soliman.
Several companies are racing to meet that challenge. Novartis has been among the most aggressive, acquiring DTx Pharma in 2023 for its FALCON platform, which uses fatty acid ligands to enhance the distribution and cellular uptake of siRNAs into muscles and the central nervous system (CNS). More recently, the company acquired Avidity Biosciences for its antibody-oligonucleotide conjugate technology — a system that links RNA molecules to antibodies that directly target muscle cells. The deal delivered three clinical-stage neuromuscular programs, including Del-zota, a treatment designed for Duchenne muscular dystrophy patients, that recently received a Breakthrough Therapy designation from the FDA.
Whoever cracks heart, lung, kidney, CNS delivery with the same precision GalNAc gave the liver will control the next wave of billion-dollar assets.
- William Soliman, Accreditation Council for Medical Affairs
In September 2025, Novartis also licensed three additional siRNA therapies: ARO-SNCA from Arrowhead Pharmaceuticals, targeting alpha-synuclein in Parkinson’s disease, and two discovery-stage candidates from China-based Argo Biopharma aimed at cardiovascular diseases, severe hypertriglyceridemia and mixed dyslipidemia.
Dicerna, a company acquired by Novo Nordisk for $3 billion in 2021, has also been innovating with its GalXC-Plus program, exploring alternative RNA structures and synthetic ligands designed to deliver RNA therapeutics to other tissues, including the CNS, muscles, adipose tissue, and tumors. Before the acquisition, GalXC-Plus had already demonstrated that siRNA could be directed beyond hepatocytes, achieving deep and sustained mRNA knockdown in neurons, astrocytes, and oligodendrocytes in preclinical studies. Building on this platform, Novo Nordisk has continued expanding extra-hepatic delivery capabilities, partnering with NanoVation in 2024 to develop long-circulating lipid nanoparticles aimed at delivering siRNA into metabolic, cardiovascular, and neurological tissues.
Advances in delivery methods like these are crucial to unlocking the full potential of siRNAs beyond the liver. “Whoever cracks heart, lung, kidney, CNS delivery with the same precision GalNAc gave the liver will control the next wave of billion-dollar assets,” noted Soliman.
Hurtling towards an RNA-based future
Other pharma companies have also entered the siRNA market recently with high hopes to treat a variety of conditions. GSK is centering its strategy on inflammatory and respiratory diseases, most notably with its October 2025 acquisition of EMP-012, an siRNA therapeutic in early trials for chronic obstructive pulmonary disease. This move builds on GSK’s earlier collaboration with Arrowhead Pharmaceuticals for ARO-HSD, an RNAi therapy in development for nonalcoholic steatohepatitis (NASH).
AbbVie and Sarepta have also joined the push. Earlier this year, AbbVie signed a $335 million deal with ADARx Pharmaceuticals for multiple siRNA programs across neuroscience, immunology, and oncology, while in July Sarepta pivoted its pipeline to focus on tissue-targeted siRNA, enabling repeat dosing and expanding into neuromuscular, pulmonary, and neurodegenerative diseases.
Taken together, these moves represent not just a collection of deals, but a coordinated shift within the pharmaceutical industry towards siRNA as a mainstream therapeutic approach. Unlike permanent gene therapies such as AAV-based approaches, siRNA offers the ability to selectively and reversibly silence disease-causing genes, giving pharma more control over dosing and safety. This is becoming increasingly important as several AAV therapies have been linked to safety risks as well as difficulties in manufacturing.
As delivery technologies continue to evolve and expand into new tissues, siRNA is poised to move further into indications that affect millions, not just thousands. The increased momentum suggests that the field is entering a new era in which gene silencing is not a scientific novelty but a routine therapeutic strategy — one that could reshape drug development across some of the most challenging disease areas of our time.
