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Without these lipid shells, there would be no mRNA vaccines for Covid-19

August 12, 2021

Fragile mRNA molecules used in COVID-19 vaccines can’t get into cells on their own. They owe their success to lipid nanoparticles that took decades to refine

A lipid nanoparticle (LNP) containing messenger RNA (mRNA) enters a cell through an endosome (right). When the LNP is inside the acidic endosome (middle), the ionizable lipids become positively charged and help release the LNP and mRNA into the cell’s cytoplasm. Once free, the mRNA is translated by ribosomes to make proteins (left).

Messenger RNA (mRNA) is having a moment. This year, hundreds of millions of people will receive shots of the Pfizer-BioNTech or Moderna vaccines for COVID-19. The crucial ingredient in each injection is mRNA, short-lived strands of genetic material that prompt our cells to start making SARS-CoV-2 proteins, which in turn help our immune systems develop antibodies that prevent future infections. Thanks to decades of scientific perseverance, billions of dollars of investment in the technology, and previous work on coronaviruses, the vaccine makers were able to design their vaccines and prove their safety and efficacy in under a year.

Related: Everything we know about the COVID-19 coronavirus

The success of these COVID-19 vaccines is remarkable and was far from guaranteed. mRNA is incredibly delicate. Enzymes in the environment and in our bodies are quick to chop mRNA into pieces, making lab experiments difficult and the delivery of mRNA to our cells daunting. On top of that, mRNA strands are large and negatively charged and can’t simply waltz across the protective lipid membranes of cells. Many scientists thought the technology would never work.

“There were many, many skeptics,” says Frank DeRosa, who began working with mRNA in 2008 and is now chief technology officer at Translate Bio, a firm developing mRNA vaccines with Sanofi. “People used to say that if you looked at it wrong it would fall apart.”

Luckily, scientists found a solution. To protect the fragile molecule as it sneaks into cells, they turned to a delivery technology with origins older than the idea of mRNA therapy itself: tiny balls of fat called lipid nanoparticles, or LNPs.

LNPs used in the COVID-19 vaccines contain just four ingredients: ionizable lipids whose positive charges bind to the negatively charged backbone of mRNA, pegylated lipids that help stabilize the particle, and phospholipids and cholesterol molecules that contribute to the particle’s structure. Thousands of these four components encapsulate mRNA, shield it from destructive enzymes, and shuttle it into cells, where the mRNA is unloaded and used to make proteins. Although the concept seems simple, perfecting it was far from straightforward.It is a tremendous vindication for everyone working in controlled drug delivery.Robert Langer, chemical engineer, Massachusetts Institute of Technology

Over more than 3 decades, promising lipids studied in the lab often failed to live up to their potential when tested in animals or humans. Positively charged lipids are inherently toxic, and companies struggled for years before landing on formulations that were safe and effective. When injected intravenously, the particles invariably accumulated in the liver, and delivery to other organs is still an obstacle. Reliably manufacturing consistent LNPs was another challenge, and producing the raw materials needed to make the particles is a limiting factor in the production of COVID-19 vaccines today.

LNP development has been a headache, but without this packaging, mRNA vaccines would be nothing. “It is the unsung hero of the whole thing,” says Giuseppe Ciaramella, who was head of infectious diseases at Moderna from 2014 to 2018.

The vaccines, appropriately celebrated as a first for mRNA technology, are also a milestone for the nanoparticle field. Although the first drug based on an LNP was approved by the US Food and Drug Administration for a rare genetic disease in 2018, the two authorized mRNA vaccines for COVID-19 present a far bigger opportunity for the nanoparticles than even the field’s founders can imagine. “It is a tremendous vindication for everyone working in controlled drug delivery,” says Robert Langer, a chemical engineer at the Massachusetts Institute of Technology.

“LNPs will be going into millions of arms over the course of this year,” says University of British Columbia nanoparticle scientist Pieter Cullis. “What was a fringe field back in the 1980s has turned into something that is mainstream now.”


Modern LNPs can be traced back to work on simpler systems called liposomes, hollow lipid spheres often made of just two or three kinds of lipids. In the early 1980s, Cullis found that cancer drugs could diffuse into these liposomes and get trapped in the hollow core. When injected into animals with cancer, the liposomes would slip through the leaky vasculature of tumors, enter cells, and unleash a drug. Cullis, and several others, started companies with the hope that liposomes could safely deliver otherwise toxic drugs into tumors in humans.

Progress was slowed by issues with stability and manufacturing. The first liposome-based drug eventually was approved by the FDA in 1995, but by then Cullis and many in the field had moved on to a new challenge: using lipid particles to deliver nucleic acids such as DNA and RNA.The devil is absolutely in the details as far as LNPs are concerned.Giuseppe Ciaramella, former head of infectious diseases, Moderna

At the time, scientists were enamored by advances in genetics that were promising to cure diseases by giving someone new genes or turning disease-causing genes off. Figuring out how to deliver these nucleic acid therapies—either DNA or RNA—into cells was a major challenge and required something more sophisticated than a conventional liposome. Cullis knew that adding positively charged lipids to the liposomes would help balance the negatively charged nucleic acids, but there was a problem. “There are no cationic lipids in nature,” Cullis says. “And we knew we couldn’t use permanently positively charged lipids because they are so damn toxic.” Those lipids would rip cell membranes apart, he adds.

A solution came from new lipids that were charged only under certain conditions. During the late ’90s and through the first decade of the 2000s, Cullis, his colleagues at Inex Pharmaceuticals, and the Inex spin-off Protiva Biotherapeutics developed ionizable lipids that are positively charged at an acidic pH but neutral in the blood. The group also created a new way to manufacture nanoparticles with these lipids, using microfluidics to mix lipids dissolved in ethanol with nucleic acids dissolved in an acidic buffer. When the streams of those two solutions merged, the components spontaneously formed lipid nanoparticles, which, unlike the hollow liposomes, were densely packed with lipids and nucleic acids. The process was simple in theory, but getting the machine to reliably spit out consistent LNPs was difficult.

LNPs that looked good in the lab often floundered in the clinic, however. The first versions of ionizable lipids were still toxic. And early formulations of the nanoparticles didn’t degrade fast enough, causing them to accumulate after repeated injections. Protiva found that one of its experimental LNP therapies caused a more severe immune reaction in humans than it had in the lab, and the company pinned pegylated lipids as a major factor.

Related: Fatty Bundles Sneak siRNA Into Cells

Pegylated lipids, in which polyethylene glycol (PEG) strands are attached to lipid heads, have several functions in a nanoparticle. PEG helps control the particle size during formulation, prevents the particles from aggregating in storage, and initially shields the particles from being detected by immune system proteins in the body, according to James Heyes, a former Protiva scientist. Heyes is now chief scientific officer of the LNP company Genevant Sciences—a firm with origins in Protiva.

But PEG also has liabilities. It prevents LNPs from binding to proteins that help shuttle them into cells. Because PEG extends particles’ life span in the body, the immune system has more time to spot the particles and start mounting an antibody response. And although PEG is found in many cosmetic, drug, and food products, scientists hypothesize that some people could develop antibodies to PEG and that giving those individuals an injection of PEG-coated nanoparticles could trigger an anaphylactic reaction.


By 2005, the development of better and safer LNPs was driven by excitement for a new technology, called small interfering RNA (siRNA), for selectively silencing genes. Alnylam Pharmaceuticals, which became the leading siRNA company, quickly realized that existing nanoparticles were not very good at helping siRNA get into cells. The company struck multiple partnerships to make new LNPs, including with Protiva in 2005 and Inex in 2006. The groups made more than 300 ionizable lipids, first optimizing the fatty tails, then tweaking the ionizable head group and the linker region in between. The work was grueling, and lipids that made great nanoparticles in a petri dish would often flop in animal studies. “You can have 50 different ionizable lipids that all deliver effectively to cells in culture, and 49 of them won’t work a damn in vivo,” recalls Thomas Madden, who worked at Inex and is now CEO of Acuitas Therapeutics.


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One Comment
  1. Elizabeth Schneider permalink

    Now why in the hell are you promoting this poison?!! Shame on YOU!!!!!

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