A surprising advanced biotech shows up in the recently released film "Spider-Man: Brand New Day." The protagonist Peter Parker goes to see Bruce Banner to stop the out-of-control strengthening of his spider gene mutation, and Banner tells him he controls the Hulk with "short interfering RNA (siRNA)."
If past Hollywood films like "Gattaca" regularly used "gene editing (CRISPR)" as a staple, the fact that siRNA now appears on screen shows the biotech industry's center of gravity has shifted.
siRNA has actually been introduced into new drug development and is used to treat patients. Novartis' hyperlipidemia therapy "Leqvio" and Alnylam's amyloidosis therapy "Amvuttra" are representative. Both are blockbuster drugs with annual sales exceeding $1 billion (about 1.4 trillion won).
Recently, as technologies have been developed to send siRNA to organs beyond the liver or to control multiple targets simultaneously with a single drug, a new competition has begun.
So how exactly does siRNA work, and how far is it evolving?
◇ The power of a "short double strand"… "interfering" with disease protein production
siRNA is short for "short interfering RNA."
First, "short" refers to a size of about 20–25 small base pairs. Structurally, it takes the form of a "double strand" twisted like a rope. When long RNA enters the body, the immune system mistakes it for a virus and attacks, but when trimmed into a "short double strand," it can slip past surveillance.
"Interfering" means stepping into the process in which genetic information is turned into protein and disrupting the work. In short, it is a technology that makes the molecule short enough to evade the body's immune response and selectively interferes with the process by which disease proteins are made.
Its mechanism is often compared to the relationship between an "original document" and a "work order."
If the body's DNA is the "original document" that carries genetic information, mRNA (messenger RNA) is the "work order" delivered into the cell to make proteins based on DNA's information. Ribosomes in the cell read this order to make proteins.
siRNA does not touch the original DNA. Instead, it finds and degrades the target mRNA at the stage before proteins are made. This triggers "gene silencing," which blocks the production of proteins that cause or worsen disease.
For this reason, the line MJ throws to Peter in the film, "You're changing your DNA right now," differs from how siRNA actually works. Unlike gene editing, which permanently modifies DNA sequences, siRNA temporarily suppresses gene expression. When the drug effect wears off, the expression of the gene can reappear.
The film's "universal inhibitor" is also far from reality. Actual siRNA is designed to match the mRNA base sequence of a specific gene, so a single drug cannot inhibit every gene.
Another challenge is "delivery." For siRNA to find the target mRNA, it must first reach the desired tissues and cells. In reality, we are not yet at the level where, as in the film, you can administer a drug with a single device and immediately pick and control only the desired genes.
◇ Beyond weight loss, improving "quality of treatment"… siRNA aims to be an obesity drug "partner"
In fact, it's been nearly 30 years since siRNA began development as a human therapeutic technology. So why the attention now?
Behind it is the rapidly growing obesity drug market.
As GLP-1 therapies such as Novo Nordisk's "Wegovy" and Eli Lilly and Company's "zepbound" have expanded the weight-loss market, industry attention has shifted to "what more can be done," such as preventing rebound, minimizing muscle loss, and reducing fatty liver and visceral fat.
Naturally, siRNA, which selectively suppresses the expression of specific genes, has emerged as a new treatment option.
A company leading in this field is the U.S. biotech Arrowhead Pharmaceuticals. Arrowhead is developing siRNA-based candidates called "ARO-INHBE" and "ARO-ALK7."
In a phase 1 trial combining ARO-INHBE with tirzepatide (the active ingredient in zepbound), an interim readout showed the combination group's maximum weight loss at week 16 was 9.4%, greater than the 4.8% with tirzepatide alone. Visceral fat fell by up to 23.2% in the combination group versus 7.4% alone, and fatty liver declined 76.7% versus 20% alone.
This shows that siRNA may not only compete with existing drugs but also complement areas where treatment is lacking.
◇ Delivery beyond the "liver limit," "multi-target" approaches that cut side effects are coming
Corporations are taking a step further by tackling delivery technologies that send siRNA to desired organs.
All eight siRNA-based therapies approved worldwide so far target delivery to the liver. Not only can drugs easily reach the liver through the bloodstream, but delivery technologies that use specific receptors on the surface of liver cells to usher siRNA into cells also developed early.
In contrast, organs where it is hard for drugs to reach the desired cells from the blood—such as adipose tissue, muscle, and the brain—require separate delivery technologies.
In Korea, OliX Pharmaceuticals(226950) is taking on this limitation. The company's recently unveiled platform, "OASIS-DUO," combines siRNA delivered to the liver with siRNA delivered to adipose tissue to suppress different genes in each organ. Simply put, it is a "2 in 1 bundled delivery" technology that ties two drugs with different destinations into one shipment.
OliX Pharmaceuticals is also expanding into the brain. Because the brain has the blood-brain barrier (BBB), which blocks external substances, drugs have traditionally been delivered via intrathecal injection with a spinal needle. OliX Pharmaceuticals has built the "OASIS-CNS" platform by adding a BBB-shuttle, and in preclinical studies succeeded in suppressing target genes by up to 70%–80% in deep brain regions such as the striatum and hippocampus with subcutaneous injection alone.
This is not the only direction in which siRNA is evolving.
Attempts are underway to suppress multiple genes at the same time with a single drug. In diseases where multiple genes are intricately intertwined, controlling several genes may improve treatment effects.
AprilBio(397030) has entered this space. AprilBio recently became the second-largest shareholder of RNA specialist 큐리진, securing related candidates.
Existing siRNA-based therapies had a critical stumbling block. Only one strand of the double strand works, and the remaining "passenger strand (passenger RNA)" wanders in the body, inappropriately triggering genes and causing side effects.
Curigin has assigned this passenger strand the mission of striking another disease gene. By harnessing the strand that caused side effects, it created a "one shot, two hits guided missile" that targets two disease genes simultaneously with a single molecule.
With siRNA appearing in the new Spider-Man film, industry and academia are calling it both fresh and welcome. On overseas online forums, everyone from students to active researchers is engaged in heated debate over the movie's scientific accuracy.
Some say siRNA technology has entered a full-fledged "blooming period," enough to captivate the big screen.
An industry official said, "In reality, siRNA technology has moved beyond validation and into the expansion phase," and predicted, "Corporations that secure delivery to diverse organs beyond the liver and multi-target control technologies will lead the market."