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.

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.

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…..

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