For all the devastation the Covid-19 pandemic has caused, there is finally a bright spot: For the first time ever, drug companies created a vaccine against a novel pathogen within a year of its discovery—about a tenth of the time it usually takes. Regulatory authorities in the US, the UK, the EU, and Canada have all authorized the Pfizer/BioNTech Covid-19 vaccine, a world-first for a vaccine based on messenger RNA. President-elect Joe Biden received his Pfizer jab on Dec. 21. A few days earlier, on Dec. 18, the US also authorized Moderna’s mRNA vaccine.
These nucleic acid vaccines, which use cells’ existing infrastructure to manufacture their own medicine, appear poised to kickstart new era of rapid-response vaccine development. But their success wouldn’t have been possible without a supportive technology that allows the shots to reach the right destination in the body: tiny bits of fat called lipid nanoparticles.
More than mRNA vaccines themselves, these lipid nanoparticles may portend big changes in pharmaceutical development. They can carry big molecular cargo like mRNA and other nucleic acids and deliver them with specificity. That ability to deliver targeted therapies could unleash a new wave of drugs with the potential to cure previously untreatable diseases.
“I’m convinced that in the next 50 to 100 years we’ll be able to solve all the [medical] problems that we have not yet,” says Sylvia Daunert, a biochemist studying nanoparticles at the University of Miami. She believes that future therapeutics will coax the body into making the tools it needs to repair itself—like a molecular surgeon traveling through the body to the point of need. “It’s not just The Magic School Bus, it’s a reality.”
Big things in small packages
Scientists have thought for decades that targeted drug delivery is the future of medicine. The problem has been figuring out how to get drugs into some cells while avoiding others.
For the latter half of the 20th century, the pharmaceutical industry was focused on small molecule drugs. The advantage of these medicines is they’re small enough to wiggle their way through cell membranes, which are composed of a protective double layer of lipids. The downside is they don’t discriminate.
“That’s a big problem because the drugs go everywhere in your body, but a very small proportion gets to where you want to go,” says Pieter Cullis, a biochemist focusing on lipid nanoparticles at the University of British Columbia in Vancouver, Canada.
The solution, some scientists thought, was lipid nanoparticles. Our bodies use little packages of fat bubbles to ferry in nutrients and ferry out waste all the time, using proteins on the outside of these packages like shipping addresses to designate the internal material’s final destination. So in the 1980s, scientists started making their own lipid envelopes for drugs, ultimately using them to deliver a handful of small molecule-based anti-cancer drugs that would target only tumor tissue.
But small molecule drugs can’t effectively treat a huge number of conditions. So in the 1990s, the industry started working on a new wave of drugs—big ones. And those big drugs needed new, bigger packages.
These big, so-called biological drugs take advantage of systems already existing in bodies: Antibodies can attack foreign or misfiring cells that shouldn’t be there; nucleic acids like DNA and mRNA can provide recipes for our cells to make their own medicine.
Antibodies don’t need to penetrate the cell membrane, but nucleic acids do. Scientists weren’t sure how to package them correctly. Molecules of this size are far too big to make it through cells’ protective membranes on their own; where small molecule drugs may have a molecular weight of 500 Daltons (a biological unit that describes the number of atoms in a molecule), nucleic acids may be in a range of hundreds of thousands of Daltons, Cullis explained.
And nucleic acid drugs, including mRNA therapies, introduced an extra challenge: Injecting any kind of foreign genetic material into the body triggers a swift immune response. To patrolling immune cells, these therapies look like another viral or bacterial threat, so they dismantle it within hours.
So scientists went back to the drawing board.
Instead of putting these drugs in a tiny bubble of fat, they designed lipid nanoparticles that are more like globules, which can bind with a nucleic acid and carry it to its targeted destination.
It wasn’t an easy process. To get nucleic acids to bond with fats, they need opposing charges, like a magnet. But nucleic acids all have a negative charge, and positively charged fats don’t exist in nature. In the early 1990s, University of California, Irvine, biophysicist Philip Felgner invented a positively charged lipid particle in the lab—but in living creatures, they wouldn’t work: “Cationic lipids are just really toxic,” Cullis says. “They rip membranes apart.”
Eventually, Cullis and his team at the University of British Columbia worked with Inex Pharmaceuticals (now Tekmira Pharmaceuticals), Alnylam Pharmaceuticals, and Acuitas Therapeutics to come with a solution (Pieter co-founded Inex and Acuitas): They could bind the negatively charged nucleic acid to the positively-charged lipid particle in a slightly acidic solution. Then, they could raise the pH to make it more neutral, like inside our bodies, while adding in a few more fat globules to surround the package. The mRNA stayed attached and intact, and the protective layer of lipids outside wouldn’t damage the cell membrane.
Acuitas Therapeutics licensed the technology to Pfizer/BioNTech for their Covid-19 vaccine. Moderna’s is similar, having licensed the technology from Acuitas in the past, but is now tailored for its own vaccine.
That’s an incredible breakthrough, and work including Cullis’ has directly led to the success of these first mRNA vaccines. But these lipid nanoparticle assemblies could also help deliver other drugs that have previously never been able to reach the right cells in patients’ bodies—or the right patients.
An unmet need
Pharmaceutical companies typically invest the most in drugs that have the biggest potential customer base. That means a smaller group of people with rare but severe diseases are often left out of the drug development process. When a drug company makes a product that does target them, the lower demand results in higher prices.
Other RNA-based therapeutics, bonded to lipid nanoparticles, could target those more specialized diseases. Alnylam Pharmaceuticals, for example, developed one such drug called Onpattro, which treats transthyretin-mediated amyloidosis, a genetic disease that deteriorates tissue in the heart. It’s caused by a misshapen protein formed in the liver. Instead of containing mRNA, it contains silencing RNA, or siRNA. This code tells cells in the liver not to produce the faulty protein associated with the disease.
In theory, lipid nanoparticles could be used to deliver immunotherapies for cancer, too. If scientists can figure out the unique antigens given off by a person’s cancer, they can use nucleic acids coding for that antigen to generate an immune response that attacks the tumor, says Francis Szoka, a bioengineer at the University of California San Francisco.
Not that it’ll be easy. For every new drug or vaccine, scientists still need to figure out how to get nanoparticles to where they need to be. Each kind of cell looks for different protein markers before letting in a medical messenger; identifying those proteins is the next hurdle.
“The reality is we got lucky,” Cullis says. When his group was designing his drug for liver cells, they found that a protein called APOE lipoprotein got stuck to their lipid nanoparticles almost right away, which helped it make it to the liver cells it needed. It wasn’t something they intentionally engineered their particles for. (There hasn’t been data collected on whether this same process helps the mRNA of Covid-19 vaccines to get into our muscle cells, but it’s likely this is the case.)
Figuring out how to get these particles into other kinds of cells, like tumor cells, is going to be harder. Compared to this year, though, scientists will think it’s a cakewalk.