Covid-19 vaccine success bolsters nanoparticle drug delivery research

Credit: Emily Wyatt, Mark Davis, California Institute of Technology. Based on research funded by the US National Cancer Institute.

In 1974, Dr. Robert Langer was part of the first cohort of researchers to begin nanoparticle research, as his lab at Cornell University developed tiny particles to deliver large molecules for angiogenesis. Since then, the field of nanomedicine has steadily progressed to reach high points such as the successful use of nanotechnology to deliver messenger RNA (mRNA)-based Covid-19 vaccines. Langer, now a David H. Koch Institute Professor at the Massachusetts Institute of Technology, and a Moderna shareholder, says “[Nanotechnology research] been steadily growing, but I think the success of the Covid-19 vaccines, which rely on nanoparticles, has accelerated it too”. 

Langer explains that nanoparticles can vary massively in formulation based on their uses. Researchers may develop nanodrugs due to their smaller surface area to allows drugs to dissolve faster, or nanoparticles may encapsulate drugs, so they last longer in the body. In the case of most mRNA vaccines, a lipid nanoparticle-based approach was chosen due to its ability to protect the mRNA in the body and prevent degradation. Covid-19 vaccines from Moderna and Pfizer/BioNTech, which use lipid nanoparticles, became the only two FDA-approved vaccines for almost all ages.

Lipid nanoparticles are spherical vehicles made from ionizable lipids. They are positively charged at low pH and become neutral within the body, reducing their toxicity. Due to their size, cells can absorb them where they release products.

Olivier Jarry, CFO of the Spanish biotech Libera Bio, says there has been a shift in the industry following the success of the Covid-19 vaccines. “Before this, people would say nanotechnology is not going to work well. Now with this example, I think they’ve seen it work extremely well, so this is a ringing endorsement that nanotechnology can make a big difference”.

In an email to this news service, João Conde, PhD, professor at NOVA Medical School, Universidade NOVA de Lisboa, said advances like the mRNA vaccines serve as a testament to the breakthroughs made by science over decades of research at the junction of genetics and nanomedicine. “This intersection will be remembered as one of the most significant achievements in science and medicine”.

Most of the initial research into nanomedicine focused on enzyme replacement therapy in the liver for enzymes such as Aspergillus niger amyloglucosidase, says Moein Moghimi, PhD, professor of Pharmaceutics and Nanomedicine, Newcastle University, Newcastle upon Tyne. With early nanoparticle studies, researchers often found the human body’s innate immune response to drugs and the short-lasting effects of drugs challenging, as they can also reduce a drug’s efficacy. However, after a period of slow movement in the field, the FDA approved the first nanodrug, Doxil, for Kaposi sarcoma in 1995. Since then, the drug has been used off-label in breast cancer and other types of cancer.

However, following an initial buzz of activity in the field and excitement surrounding the approval, Moghimi says “things took a nosedive for a few years”. The next wave came from early research into liposomes and lipid nanoparticles, both of which are used for drug delivery. He says, “It gave a new lease [on] life to the field”. Liposomes have the same function as lipid nanoparticles in drug delivery but have a simpler formulation. Liposome research paved the way for the design of current lipid nanoparticles. 

Lipid nanoparticle drug delivery was in the spotlight during the Covid-19 pandemic. Moderna’s Spikevax and Pfizer BioNTech’s Comirnaty vaccines use lipid nanoparticles to encase the nucleic acids in the mRNA vaccine. Langer’s engineering lab was instrumental in the development of these lipid nanoparticles, playing into his role in co-founding Moderna. These vaccines have proven to be blockbusters, with Moderna earning $18.4 billion in Spikevax sales in 2022, and Comirnaty generating $37 million for Pfizer in 2022. GlobalData predicts that Comirnaty’s sales will increase by more than 20% between 2024 and 2027. 

GlobalData is the parent company of Pharmaceutical Technology.

Apart from lipid nanoparticles, nanoparticle-related innovation is also reaching other types of drug development. Conde says the use of nanoparticle delivery for gene therapies has become more common over recent years. “Nanoparticles can be tailored to target specific cells or tissues, release gene therapies in a regulated manner, reduce toxicity, and increase stability,” he added. 

Moghimi’s lab is also developing nanoparticle drug systems to help drugs cross the blood-brain barrier, a feat that has not yet been achieved. If successful, such applications could be used for neurodegenerative conditions like Alzheimer’s disease. 

Libera Bio is using these nanocarriers, developed by the company’s cofounder MJ Alonso, PhD, professor, Department for Pharmacy and Pharmaceutical Technology, Universidade de Santiago de Compostela, to deliver antibodies. Unlike mRNA vaccines, a lipid nanoparticle approach cannot be used for delivering antibodies as they vary too much in size and have both hydrophobic and hydrophilic areas, says Jarry. Thus, Jarry explains that Libera is developing multifunctional polymeric nanocapsules (MNPs) that use a lipid, an aqueous medium, and polymer nanoparticles. This design protects antibodies from the innate immune system. The outer layer of the carrier can have ligands added to it so it can target specific cells. He adds that this structure can deliver a small molecule inside the lipid phase and an antibody inside the aqueous phase.

“For diseases that are based on cell dysfunction, 75% [of targets] may be inside the cell and 25% on the cell surface. And the issue is that antibodies are too big to go directly inside the cell,” he says. He also says this is great for drugs like Bristol Myers Squibb’s Opdivo (nivolumab) and Merck’s Keytruda (pembrolizumab), which target cell surface receptors, but it is difficult to select a range of other targets to treat diseases. Jarry expects to take the MNPs into the clinic in two years. “We want this product to go to clinic, but we are more into designing the nanocarrier right now, so the sooner a big pharma takes them [the nanocarriers] for further development, the better,” he says.

Langer’s lab is working on a range of drug delivery systems at the nanoscale level that can encapsulate nutrients for the developing world, or develop “self-boosting vaccines” and more. He describes self-boosting vaccines as those that deliver an immunogen at set times. While still in preclinical studies, Langer’s lab is also investigating oral pills with an effect that can last longer than one week.

Still, several established challenges remain. “Lipid nanoparticles are one of the most promising delivery vehicles for nucleic acid-based therapies, but their production and utilization are fraught with difficulties. Stability, scalability, immunogenicity, targeting, and cost-effectiveness are issues,” Conde says. “It takes a long time to develop these types of formulations, because they're very complex multicomponent [drug delivery systems] that are totally different from standard drugs,” Moghimi adds.

Despite these problems, Moghimi predicts that nanoparticles will continue to make an impact in the future, especially lipid nanoparticles. “There are still possibilities that these types of nanoparticles could be used for a whole range of nucleic acid medicines, whether mRNA, DNA, or CRISPR Cas9… for different genetic diseases. These could feature in the next four to five years. Having these types of formulations would help the field of nucleic acids flourish,” he says.