Latest research on RNA therapeutics

he word ‘mRNA’ still sends shivers down the spine of many people who associate it with the Covid mRNA vaccine. New developments in mRNA therapeutics will make it vastly safer than the original. However, barriers still remain to restoring public confidence.

RNA technologies include messenger RNA (mRNA), antisense oligonucleotides, small interfering RNAs (siRNA), short hairpin RNA (shRNA), circular RNA (circRNA),^[1] and micro RNA (miRNA, which is small non-coding RNA that regulates protein expression). Collectively they’re called RNA therapeutics. Almost all use lipid nanoparticles to protect the mRNA and deliver it across the cell membrane.

The main use of these RNA molecules is to express some protein or suppress the natural expression of a protein. A significant problem is the difficulty of transporting lipid nanoparticles into specialized organs such as the brain and bone marrow. Exclusion from the marrow limits the use of mRNA in treating acute myeloid leukemia.^[1] The low rate of crossing the blood-brain barrier (BBB) limits it for brain disorders.

siRNA and shRNA to suppress unwanted proteins

Suppressing pathogenic gene expression is perhaps the commonest use of RNA, at least in the lab. You identify a ‘bad’ protein, create an RNA to stop it from being expressed, and then—often the hard part—figure out how to get the RNA to the target organ.

Getting siRNA into the brain may be the biggest challenge (don’t tell Big Pharma, but bifunctional antibodies are never going to work). To get your RNA across the BBB, conventional lipid nanoparticles don’t work. You’d have to inject it intrathecally into the cerebrospinal fluid, a risky procedure. Getting something across the BBB is easy in a mouse, but much harder in a human. The main obstacle is understanding the pathogenesis. Without that, one can only guess about which protein is unwanted.

For example, Rajbanshi et al.^[2] suggest using siRNA to block tau expression in Alzheimer’s disease (AD). These authors consider AD to be a tauopathy. If so, then blocking expression of tau could benefit patients. Perhaps because tau is necessary for motor and cognitive function ^[3], belief that tau causes AD is a minority opinion. It’s worth testing, but if tau isn’t involved in the pathology it will fail.

mRNA gain of function

mRNA technology is a gain-of-function technology because one modified mRNA molecule could produce an almost unlimited amount of some desired protein. This violates the first principle of pharmacology: too much is as bad as too little. As the saying goes, the dose makes the poison. Yet doctors in clinical settings rarely adjust their prescriptions to match the patient’s weight or body surface area (BSA) because it’s inconvenient to make many different sizes of every drug, and because (as I found while training them) doctors are generally not very confident with their math skills.

There are many unsolved problems with mRNA drugs. One is that only 10% of the RNA can escape the endosomes and get translated. Another is that mRNA expression is non-linear. Twice the dose might mean a huge increase in side effects because excess dosage or injections that miss the muscle get into the bloodstream. Modified mRNA, unlike normal mRNA, can be expressed for weeks or more. This means some patients will praise mRNA for its safety because they experience no adverse effects, while others can experience permanent disability. The only way to know how much protein is produced is to measure it repeatedly over time, which is very expensive.

Another unsolved problem is how to convince drug companies to use something harmless as their antigen instead of the toxic spike protein. One shudders to think what they'd use to vaccinate us against something like diphtheria. (Diphtheria toxin, a 70 kDa protein, is one of the most toxic substances known but it would probably make a terrific antigen.)

Passive immunization

Instead of using mRNA to express a toxic protein and hoping the body generates good antibodies, in passive mRNA immunization the RNA expresses the antibody itself. Crude versions of mRNA-coding antibodies were used against Covid in Moderna’s mRNA-1940. If it worked efficiently, it would be a rapid and cost-effective way of building up immunity in patients. It would also be useful in immuno­therapy for cancer patients, who receive hundreds of milligrams of expensive purified antibody by infusion, risking infusion reactions.

Many types of cancer treatment, such as chemotherapy and radiation, cause secondary immuno­defic­iency.^[4] In such patients, passive immunization might be the only option. If we could harness the immune system instead of working against it, it would bring us out of the dark ages of DNA-smashing drugs.

The biggest problem with all such mRNA techniques is that control of expression of RNA administered as nanoparticles is currently almost nil. Drugs only only available as ‘none’ or ‘a massive unknown amount’ have limited value. Indeed, some immunotherapies, such as CAR-T cell therapy, can produce immune T-cell exhaustion, which is also suspected as a cause of long Covid.^[5] Suppression of pattern recognition receptor signaling, which is necessary for mRNA vaccines to work, can also increase the reactogenicity of the mRNA.

Next-generation mRNA

A new generation of mRNA, still mostly in the wishful thinking stage of development, will be practically tiny computers: they will respond to physiological triggers such as pH, enzyme activities, or oxygen levels as well as exogenous stimuli such as magnetic fields ^[6] or ultrasound ^[7] to improve targeting of nanoparticles. This will enable, as one paywalled paper says,

. . . controlled, site-specific, and temporally regulated mRNA release. This dual responsiveness enhances therapeutic efficacy by improving mRNA stability, bioavailability, and minimizing off-target immune activation. . . .

These are the technology advances we urgently need, but it will take years to develop them and prove to the public that they can be trusted. Unfortunately, for the most part the emphasis is still on uncontrolled mRNA expression. This is the conventional view and it is depressing:

Lipid nanoparticles (LNPs) are developed as a safe, efficient, and clinically validated non-viral delivery system that encapsulates nucleic acids by electrostatic association with ionizable lipids and releases their cargo within endosomes at acidic pH.^[8]

Despite this (possibly peer-reviewer-mandated) praise, this author mentions alternatives like mRNA to express decoy receptors for the virus. Decoys might be better than a passive antibody as they would be unaffected by virus mutation. More imagination and less rosy self-congratulation are always prerequisites for invention.

Clinical drug trials

Medical and public health professionals mostly recognize that the credibility of their profession took a heavy blow during Covid. The main problem was their support of coercion to vaccinate the population, violating the sacred principle of informed consent.

Another problem is that drug companies carry out clinical trials on their own product. Companies spend billions, experience failure, then give up and drop an entire class of diseases. Other companies slice and dice their population—or double the subject population repeatedly—until something comes out statistically significant. They might get their drug through the FDA, but no amount of statistical fudging can make a useless drug cure a patient.

But what is the alternative? Who else can do clinical drug trials? The credibility of government and academia are only marginally higher than that of the drug companies. Something new is needed.

Laymen must also be able to learn the science so they can make informed decisions. Too much of the science is paywalled, and many authors are afraid to express doubts for fear of treading into political topics. Patients are geniuses at detecting when a political appointee is giving them a snow job. If they lack access to credible information, they will either blindly obey whatever the doctor tells them or avoid the medical system entirely. Either way, they will suffer the conse­quen­ces: an FDA approved drug can kill you as effectively as any disease.

may 11 2026, 2:20 pm