Lipid nanoparticles in COVID-19 mRNA vaccines – ICAN fails science

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This article about lipid nanoparticles in COVID-19 mRNA vaccines is by VaultDwellerSYR, a pseudonym used by a faculty member of a School of Pharmacy within a large medical school. They have significant research and publications on the effect of certain chemicals on the brain. Although we are opposed to all arguments from authority, the author has a substantial record of actual, published research in this field of brain cell biology and biochemistry. 

The anti-vaccine Del Bigtree‘s Informed Consent Action Network (ICAN), as expected, started to seed doubts and fallacious claims on COVID-19 mRNA vaccines, in an attempt to discredit and reduce the uptake of this vaccine by the population.

In their latest stunt, ICAN posted on January 17th on their Facebook page the following statement with a “legal update” pictogram:

ICAN INQUIRES WITH THE FDA ABOUT THE SAFETY OF LIPID NANOPARTICLES USED IN PFIZER’S AND MODERNA’S COVID-19 VACCINESICAN, through its attorneys, has once again written to Dr. Peter Marks, Director of the FDA’s Center for Biologics Evaluation and Research, to demand a response to the question of whether or not lipid nanoparticles used in both of the currently authorized COVID-19 vaccines are safe. 
ICAN is aware that both Pfizer and Moderna have used lipid nanoparticles (“LNPs”) in their vaccines – LNPs are what the manufacturers use to surround the RNA so that it does not fall apart when injected and before reaching its target cells. Some have compared these LNPs to a fatty envelope or a delivery vehicle to get the mRNA into the human body in one piece.

A concern arose when ICAN was alerted to a study published in 2018 titled Lipid Nanoparticles: A Novel Approach for Brain Targeting. The study states: “…lipid nanoparticles are taken up readily by the brain because of their lipophilic nature. The bioacceptable and biodegradable nature of lipid nanoparticles makes them…suited for brain targeting.” The article also states, “these nanostructures need to be investigated intensively to successfully reach the clinical trials stage.”
ICAN wants to fully understand whether the evidence that these LNPs are easily taken up and end up in the brain is a safety concern with these two particular vaccines. ICAN, through its attorneys, led by Aaron Siri, has therefore sent a letter to Dr. Peter Marks, the Director of the Food and Drug Administrations’ Center for Biologics Evaluation and Research. If you recall from previous legal updates, Dr. Marks has referred to himself as “the FDA point person on COVID-19 vaccines” and has assured Americans that the FDA “will make sure they’re safe and effective.” 

ICAN also pointed out to Dr. Marks that there appears to be support for the proposition that the body may react strongly to a second dose of the LNPs. Stated differently, the body is primed to have an immune reaction to the LNPs with the first dose. As explained by Johns Hopkins, “Side effects were more frequent after the second dose in the vaccine trials.” Another article, titled Exogenous nanoparticles and endogenous crystalline molecules as danger signals for the NLRP3 inflammasomes, supports that the increasingly inflammatory side effects observed in those who received the vaccine in Pfizer’s and Moderna’s clinical trials are attributable to the LNPs and that these side effects get worse with repeated injection. We have seen this increased “reactogenicity” clearly in the data from both Pfizer’s and Moderna’s COVID-19 clinical trials. 
ICAN continues to ask the hard questions of Dr. Marks and others: If LNPs from the vaccine, which contain mRNA, are entering brain tissue, and an immune reaction is occurring during the second dose to these LNPs, does this pose a safety concern for vaccine recipients? ICAN asked Dr. Marks to consider the question posed and provide support for the substance of any response he provides.

ICAN will closely review any response from Dr. Marks given his promise that he and the FDA “uphold globally respected standards for product quality, safety, and efficacy” and his statement that he would resign if “something that was unsafe or ineffective [] was being put through.” As always, ICAN offered to provide any additional information or to meet with Dr. Marks to discuss this issue.

As you can see, ICAN is on one of another PR stunt in the attempt to “cease and desist”, as intimidation with little legal merit and certainly not based on an honest and critical review of the existing literature. Let’s critically examine ICAN’s claims about lipid nanoparticles.

What is ICAN’s concern about lipid nanoparticles?

The following statement is interesting for several reasons:

A concern arose when ICAN was alerted to a study [sic] published in 2018 titled Lipid Nanoparticles: A Novel Approach for Brain Targeting. The study states: “…lipid nanoparticles are taken up readily by the brain because of their lipophilic nature. The bio-acceptable and biodegradable nature of lipid nanoparticles make them…suited for brain targeting.” The article also states, “these nanostructures need to be investigated intensively to successfully reach the clinical trials stage.”

The first thing to note is that ICAN apparently cannot make a difference between a “study” (which is structured around an initial hypothesis, methods to address the hypothesis, and results that prove or refute the hypothesis) and a “review”, which is a summary of existing literature on a topic, usually aimed to give an overview and discuss the current state of affairs on a particular subject.

In this case, they are citing a review by Sankar and colleagues published in Pharmaceutical Nanotechnologies in 2018 (Reference 1). This is a journal that harbors a SCIMago SJR score of 0.24 and an H-index of 4, by comparison, the AAPS Journal, the official journal of the American Association of Pharmaceutical Sciences harbors a SCIMago SJR score of 1 and an H-index of 100. It is also important to note that ICAN decided to cite a review published in 2018 in 2021, which means they overlooked 3 years of literature.

I don’t know if they deliberately cited such a review because they thought it aligned with their pre-formatted conclusion, or if they just picked the first hit that came on their search engine (Google, Pubmed). One thing that is interesting to note is that they have been citing the review on what seems solely based on the abstract, as I have highlighted the quote from the abstract:

Background: Brain is a delicate organ, separated from general circulation and is characterized by the presence of a relatively impermeable Blood-Brain Barrier (BBB). The BBB maintains homeostasis in the brain thus restricting the entrance of foreign bodies and several molecules from reaching the brain. As a result several promising molecules do not reach the target site and fail to produce in vivo response. Nevertheless, lipid nanoparticles are taken up readily by the brain because of their lipophilic nature. The bioacceptable and biodegradable nature of lipid nanoparticles makes them less toxic and suited for brain targeting.

Objective: In the present review the BBB, mechanism of transport across the BBB, strategies to bypass the blood-brain barrier have been presented. The aptness of lipid nanoparticles for brain targeting has been highlighted. The proposed mechanism of uptake of the lipid nanoparticles, methods of prolonging the plasma retention and various methods of preparation for formulation of effective delivery systems for brain targeting have been included and dealt in this review.

Conclusion: Lipid based formulations can be designated as the current and future generation of drug delivery systems as these possess tremendous potential to bypass BBB and reach the target site due to their small size and ability to dodge the reticular endothelial system. However, these nanostructures need to be investigated intensively to successfully reach the clinical trials stage.

I can conclude two things:

  1. They likely either did not read the full review or had access to it (I could not access it either, because I have no access to it via my institutional account).
  2. Citing a peer-reviewed study (or review) solely based on an abstract is gross negligence that you learn while in graduate school not to do. So much for the investigative nature of ICAN. You should never ever cite a piece of literature just based on the abstract. It is your obligation to read the full-text in order to cite that source.

But let’s move beyond the questionable claim of ICAN and see what the literature is as of today at the use of nanoparticles for bypassing the blood-brain barrier and deliver drugs into the brain (Reference 2).

What are lipid nanoparticles and why are they used to deliver drugs into the brain?

Lipid nanoparticles are small spherical particles harboring a diameter ranging from 1-100 nm made of lipids. For those not familiar with cell biology, our cells (and any living cells, from an Archaea to a human cell) are separated from the outside by the presence of a cell membrane made of two layers of phospholipids. These phospholipids harbor overall the same structure (see below): two chains of fatty acids (made of carbon and hydrogen atoms) “tails” that look like a hairpin, and a hydrophilic “head” that is made of a polar molecule (glycerol, ceramide…). This is what a regular phospholipid in your cell membrane looks like:

By SuperManu – Own work, CC BY-SA 3.0.

If you have been preparing salad dressing with vegetable oil and vinegar, you likely notice that the oil droplet would aggregate together into one big slick, whereas you will notice a clear interface between the vinegar and the oil slick. This is because the lipids present in the vegetable oil will align their hydrophobic tails inside the droplet and expose their hydrophilic head outside to interact with the water molecules of the vinegar. This is what we call “micelles”. If you work hard enough, you can create structures called “liposomes” that are able to cage water and solutes within the oil slick, separating from the rest of the water of the vinegar by having a lipid layer.


These structures look very similar to what we would see with cell membranes: a sack of water trapped inside a grease globule. Because of the lipophilic nature of the cell membrane, if you have a small molecule that is also lipophilic, it can easily cross the membrane and enter the cell very easily.

This is a property used when we design drugs. It works most of the time….except when you want to have drugs enter inside the brain. There is a serious obstacle to cross the brain and it is called the “blood-brain barrier” (BBB).
The BBB is a formidable cellular barrier that will reject over 95% of chemicals we call “small molecules” and virtually 100% of any biomolecules (be it proteins, sugars, or nucleic acid-like an RNA strand). Drug delivery across the BBB remains possibly a 50-year challenge, still undefeated despite immense efforts done by my peers (yes, I am an academic scientist working on the BBB).

The original publication by Spigelman and colleagues (Reference 2) used an incredibly high amount of polysorbate 80 (12 mg/kg or more) injected at the base of the brain (carotid artery) in mice, to increase the uptake of etoposide (an old-generation anti-cancer drug) to 2021, finding nanoparticles to cross the BBB and deliver its cargo remains as of today a challenge undefeated.

None of them until now was able to find their way from the bench to the bedside. The translation of findings from animals to humans remains a huge pitfall in biomedical research, and as of today remains a divide left uncrossed.
If ICAN was credible in their literature search, they will have likely crossed the work of Pr. Margaret Hammarlund-Udeanes (Uppsala University, Sweden) is an authority figure in the pharmacokinetics of CNS drugs. She has recently published a review (Reference 3) setting the challenges and consideration we have to face when considering nanoparticles delivery across the BBB as summarized in her finding below:

As you can see, even injected IV, the amount of methotrexate-loaded nanoparticles capable to cross into the brain and remains as unbound is very very small and requires formidable amounts (2.3-15 mg/kg of nanoparticles injected by IV infusion, only 1/1000th of the amount infused was detected in the brain).

What about the lipid nanoparticles used in the Moderna and Pfizer vaccines?

Pfizer and Moderna COVID-19 mRNA vaccines are the first authorized under an emergency use authorization (EUA) although major issues are reported in the Phase IV trials which are basically monitoring serious adverse events following authorization.

Both are using lipid nanoparticles (LNPs) as their mRNA delivery carrier, and each of them use amino-lipids of different origins: Pfizer is utilizing the technology from Acuitas Therapeutics which is based on one of the following compounds published in their 2012 and 2013 studies respectively (References 4 and 5):


Whereas Moderna went with an in-house version of their initial amino lipid (MC3) and refined it to obtain the current lead compounds used in their formulation, with speculation that Lipid M is the final candidate used in their COVID19 vaccine (Reference 6).

Two keys issue you have to think about if you want to show these lipid nanoparticles are safe from crossing the BBB:

  1. That they escape the injection site (muscle tissue) fast and at a high amount (to avoid degradation and/or absorption by the surrounding muscle tissue which possesses a high surface/volume ratio)
  2. That the stability of these LNPs is long enough to have a chance to circulate and interact with the BBB.

If you look at the Moderna vaccine LNPs, you can see that:

Despite given at a dose similar to other LNPs given by IV infusion (we are about ~10-20 mg/kg IM injection), the amount found circulating and trapped into highly vascularized tissues (liver, spleen) is pretty low (~500 µg/kg, assuming this is a cumulative accumulation),
  2. The half-life of these compounds is very short. By 12 hours, we are reaching levels below detection suggesting a complete elimination by the body.

In particular, the fate of Lipid M is the best-case scenario and suggests this is the formulation used in the mRNA vaccine by Moderna.

The second thing that ICAN could have done, if they were sincere in their procedure is to look at the existing literature preceding these compounds both in pre-clinical models (rodents, non-human primates) and clinical models (Phase I/II, and III trials).

If something occurred at the BBB resulting in the impairment of the barrier function and/or penetration of nucleic acid inside the brain, you would expect three types of reaction:

  • brain swelling from vasogenic edema and/or cytotoxic edema due to the interaction of these LNPs with the BBB.
  • brain swelling from a cytokine storm after the reactogenicity of the immune system to the spike S-protein that could be expressed at the BBB if the lipid nanoparticles ended up being expressed.
  • encephalitis inherent to the activation of an immune response inside the brain by microglial cells or by the activation of molecular patterns (pathogen as PAMPs, or damage-associated as DAMPs).

You can look up the literature and the applications packets submitted to the FDA by both companies and you will notice ZERO cases of any of these conditions were reported in their clinical trials, with at least 2 months of follow-up after 2 doses administered (you will also notice the absence of antibody-dependent enhancement or ADEs).

Instead of asking to show the safety of the LNPs as ICAN wrote, what about showing the evidence of toxicity or danger associated with these vaccines. With millions of patients vaccinated and years of studies to perfect and assess the safety of the drugs, it is very likely that these LNPs are overwhelmingly safe. In addition, if you have to look at the pharmacokinetics standpoint, these lipid nanoparticles are indeed very bad candidates due to their short-lived pharmacokinetics.

lipid nanoparticles


As expected, with a well-documented history of lies, half-true or complete fallacious claims, ICAN demonstrate to us one more time that:

  1. They are not interested in facts.
  2. They are not savvy in having an objective and critical review of the literature cited and will not even consult it before firing their FOIA requests.
  3. Ironically, they provide neither an informed (it is mostly misinformed) consent to their readers and viewers, by feeding them lies and fallacious claims aimed to seed doubt and scramble their ability to hold a true informed consent when proposed a medical procedure that is potentially life-saving (the Phase III clinical trials of both vaccines showed reduced fatalities and severity of the disease compared to their respective saline-placebo controlled group).

They surely CAN lie, CAN mislead, and CAN prop a strawman but they absolutely CANNOT do science anytime.


The author has stated that he has no conflict of interest to disclose.


  1. Shankar R, Joshi M, Pathak K. Lipid Nanoparticles: A Novel Approach for Brain Targeting. Pharm Nanotechnol. 2018;6(2):81-93. doi: 10.2174/2211738506666180611100416. PMID: 29886842.
  2. Spigelman MK, Zappulla RA, Johnson J, Goldsmith SJ, Malis LI, Holland JF. Etoposide-induced blood-brain barrier disruption. Effect of drug compared with that of solvents. J Neurosurg. 1984 Oct;61(4):674-8. doi: 10.3171/jns.1984.61.4.0674. PMID: 6470777.
  3. Hu Y, Hammarlund-Udenaes M. Perspectives on Nanodelivery to the Brain: Prerequisites for Successful Brain Treatment. Mol Pharm. 2020 Nov 2;17(11):4029-4039. doi: 10.1021/acs.molpharmaceut.0c00881. Epub 2020 Oct 16. PMID: 33064009; PMCID: PMC7610229.
  4. Jayaraman M, Ansell SM, Mui BL, Tam YK, Chen J, Du X, Butler D, Eltepu L, Matsuda S, Narayanannair JK, Rajeev KG, Hafez IM, Akinc A, Maier MA, Tracy MA, Cullis PR, Madden TD, Manoharan M, Hope MJ. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem Int Ed Engl. 2012 Aug 20;51(34):8529-33. doi: 10.1002/anie.201203263. Epub 2012 Jul 10. PMID: 22782619; PMCID: PMC3470698.
  5. Maier MA, Jayaraman M, Matsuda S, Liu J, Barros S, Querbes W, Tam YK, Ansell SM, Kumar V, Qin J, Zhang X, Wang Q, Panesar S, Hutabarat R, Carioto M, Hettinger J, Kandasamy P, Butler D, Rajeev KG, Pang B, Charisse K, Fitzgerald K, Mui BL, Du X, Cullis P, Madden TD, Hope MJ, Manoharan M, Akinc A. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol Ther. 2013 Aug;21(8):1570-8. doi: 10.1038/mt.2013.124. Epub 2013 Jun 25. PMID: 23799535; PMCID: PMC3734658.
  6. Hassett KJ, Benenato KE, Jacquinet E, Lee A, Woods A, Yuzhakov O, Himansu S, Deterling J, Geilich BM, Ketova T, Mihai C, Lynn A, McFadyen I, Moore MJ, Senn JJ, Stanton MG, Almarsson Ö, Ciaramella G, Brito LA. Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines. Mol Ther Nucleic Acids. 2019 Apr 15;15:1-11. doi: 10.1016/j.omtn.2019.01.013. Epub 2019 Feb 7. PMID: 30785039; PMCID: PMC6383180.

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Lifetime lover of science, especially biomedical research. Spent years in academics, business development, research, and traveling the world shilling for Big Pharma. I love sports, mostly college basketball and football, hockey, and baseball. I enjoy great food and intelligent conversation. And a delicious morning coffee!