Can lipid nanoparticles (LNPs) carrying the Covid-19 mRNA vaccine penetrate the blood-brain barrier? The consensus is that they are not intended to do so.

Concerns have been raised by researchers regarding the potential for the Covid-19 mRNA vaccine, which is delivered in lipid nanoparticles, to reach the brain. This stems from the capability of LNPs to transport medications across the blood-brain barrier (BBB).

In my earlier article, “Concerns of Lipid Nanoparticle Carrying mRNA Vaccine into the Brain: What to Make of It?” published in March 2021, I examined various perspectives on this issue and concluded that it is not a significant concern. Let's revisit the topic and explore recent findings.

What Was the Initial Concern? Dr. Jacob Wes Ulm, a geneticist focused on gene therapy, highlighted the lack of biodistribution data related to the LNP-encapsulated mRNA vaccine. (All references to mRNA vaccines in this context pertain to those used against Covid-19.)

The worry was that if LNPs were to transport the mRNA vaccine into the brain, neurons might produce spike proteins from the mRNA, which could trigger an immune response. This might lead to the immune system targeting neurons for destruction after multiple vaccinations.

Dr. Ulm's hypothesis did not solely concern brain cells but could apply to any body tissue where the mRNA vaccine might be delivered. His focus on the brain arose from the fact that certain LNP formulations are designed to cross the BBB, which typically prevents foreign substances, including drugs and pathogens, from entering the brain.

A summary of Dr. Ulm's hypothetical concern appeared in a rapid response published in the British Medical Journal in March 2021.

More recently, Dr. Botond Z. Igyártó and colleagues voiced similar apprehensions regarding the off-target effects of mRNA vaccines. In a paper published in Current Opinion in Virology in June 2021, titled “Future considerations for the mRNA-lipid nanoparticle vaccine platform,” they stated:

> Based on the current mRNA-LNP vaccine design, LNPs can be taken up by almost any cell type, near or far from the site of injection, transfecting them with the antigen-encoding mRNA. Moreover, the mRNA used in these vaccines are nucleoside-modified to decrease inflammatory responses and increase its stability in vivo, allowing extended periods of mRNA translation. Also, a significant portion of the mRNA can be re-packaged and expelled from transfected cells in extracellular vesicles (EVs). These vesicles could reach cells far from the injection site, further increasing the number of cells translating the antigen and extending the duration of its expression.

Thus, akin to Dr. Ulm, Dr. Igyártó and his team speculated that the mRNA vaccine might inadvertently affect unintended tissues, known as off-targets, which could lead to unforeseen outcomes.

Addressing the Brain Biodistribution Concern Animal studies using luciferase visualization have indicated that off-target effects are minimal. Most of the mRNA vaccine is localized in the muscles (at the injection site), liver, spleen, and lymph nodes, with only trace amounts in organs such as the heart and brain.

These findings align with assessments from the European Medicines Agency (EMA) and a recent Japanese biodistribution study.

For instance, the EMA report on Moderna’s mRNA vaccine noted:

> Low levels of mRNA could be detected in all examined tissues except the kidney. This included heart, lung, testis, and brain tissues, indicating that the mRNA/LNP platform crossed the blood/brain barrier, although to very low levels (2–4% of the plasma level). Liver distribution of mRNA-1647 is also evident in this study, consistent with literature reports that liver is a common target organ of LNPs. The mRNA constructs were not measurable after a maximum of 3 days in tissues other than the muscle, lymph nodes, and spleen (~25 hours in brain).

For Pfizer’s mRNA vaccine, the EMA report stated:

> Over 48 hours, distribution from the injection site to most tissues occurred [presumably including the brain], with the majority of tissues exhibiting low levels of radioactivity. Total recovery (% of injected dose) of radiolabeled LNP+modRNA outside the injection site was greatest in the liver (up to 21.5%) and was much less in spleen (~1.1%), adrenal glands (~0.1%), and ovaries (~0.1%).

The Japanese biodistribution study indicated that 0.02% and 0.009% of the administered dose of the Pfizer vaccine ended up in the brain at 2 hours and 48 hours, respectively.

While there is acknowledgment of tiny traces of the mRNA vaccine detected in unintended tissues, including the brain, clinical signs of neurological toxicity have not been reported.

How Long Do They Stay? The EMA indicated that Moderna’s mRNA vaccine is undetectable in the brain after approximately 25 hours. The Japanese study noted only 0.009% of the mRNA vaccine could be found in the rat’s brain at the 48-hour mark, which rounds off to 0%. Additionally, luciferase studies suggest that the mRNA vaccine's protein production lasts only a few days.

The mRNA vaccines are fragile and require extreme cold storage: Moderna’s and Pfizer’s vaccines must be kept at -15 to -25 °C and -60 to -90 °C, respectively. Given that human body temperature is 37 °C, the mRNA cannot survive long. Moreover, the mRNA dosage is limited, meaning cells will cease translating the mRNA into proteins once the supply depletes.

In summary, while Covid-19 mRNA vaccines can enter the brain, the quantities are so minimal that they are unlikely to cause harm and are cleared within days.

Addressing the Brain Tropism Concern Why is it challenging for the mRNA vaccine to enter the brain? (Tropism pertains to the inclination of biological entities to migrate toward specific targets, such as SARS-CoV-2's propensity to infect the lower respiratory tract.)

Dr. Goh Kiang Hua theorizes that the mRNA vaccine's journey to the brain from the injection site is not straightforward.

The vaccine is administered intramuscularly in the arm, where the muscles are rich in blood vessels and cells capable of absorbing the mRNA vaccine. If some LNPs evade this dense cellular environment and enter the bloodstream, they must withstand significant pressure as the heart pumps blood throughout the body.

“The left ventricle [of the heart] will expel the blood (with the LNPs) with great speed and force out into the aorta. If the LNPs disintegrate from the turbulence, the mRNAs will be rapidly destroyed by ribonucleases,” Dr. Goh explained. “[But] those that remain intact will be sent to the entire body.” He cautioned that “the structural integrity of these LNPs after being expelled from the left ventricle is questionable.”

Furthermore, the LNPs used in mRNA vaccines differ from those designed for drug delivery to the brain. The latter are typically positively charged (cationic), which enhances their attraction to the negatively charged cell membranes, unlike the neutrally charged LNPs in mRNA vaccines.

In a forthcoming paper in Drug Discovery Today, Bartlomiej Szabat-Iriaka and Marc Le Borgne write:

> Cationic lipid NPs (LNPs) are frequently used as drug delivery systems because they can enter cells more easily compared with anionic NCs. However, cationic LNPs are generally more toxic than anionic LNPs. [Cationic] LNPs are likely to increase brain vascular volume, cause BBB damage, and potentially lead to the formation of cerebral edema. Some NMs, such as mRNA vaccines, contain optimized LNPs with an ionizable surface charge that is supposed to remain neutral at physiological pH. However, it cannot be ruled out that this surface charge might change in individuals with conditions that can cause pH variations. Thus, toxicity risks resulting from NM interactions with the BBB are not negligible.

While the risks are acknowledged, they remain speculative without experimental data to support them.

In this regard, conditions affecting the body's pH include respiratory acidosis from chronic obstructive pulmonary disease, severe obesity, or brain injury; metabolic alkalosis from vomiting or diuretic use; and respiratory alkalosis from panic attacks or pulmonary embolism.

The mRNA vaccine consists of mRNA encapsulated within LNPs, primarily composed of neutral lipids. Some cationic lipids are present to facilitate mRNA entry into cells, but they do not significantly alter the overall charge of the LNPs.

These cationic lipids are not formulated for delivery across the blood-brain barrier, which requires different characteristics, such as additional coatings with hydrophilic polymers or specific receptors.

In Conclusion LNPs are not exclusively designed for drug delivery to the brain; they have various medical applications.

As highlighted in a 2021 Nature Reviews Materials paper, the FDA has approved several LNP-based treatments for conditions such as cancer and fungal infections.

The Covid-19 mRNA vaccines from Moderna and Pfizer are FDA-approved LNP-based products that are not intended to cross the blood-brain barrier. While minimal traces of the mRNA vaccine have been observed in the brain and other unintended tissues, the amounts are negligible and unlikely to cause significant effects.

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