Cloaking a cure: Lipid capsules save the world

By Stacy Kish

In This Section

February 2023

The Moderna and Pfizer COVID-19 vaccines were developed to prevent disease caused by the SARS-CoV-2 virus. These vaccines rely on mRNA, a snippet of genetic code that only contain instructions for how to make a spike protein—the antennae-like protrusions that extend from the surface of the virus’s cell membrane. The spike protein plays an integral role in how the virus gains entry into the host cell. By recognizing the initial attack, a vaccinated person can mount a defense to the virus, triggering an immune response that produces a cascade of antibodies. As a result, a vaccinated person experiences a less severe form of disease and shorter duration of the illness.

There is one problem. How do you get the snippet of genetic code, which is unstable on its own, into the host cell to impart protection?

The answer is a sleek lipid capsule, called a lipid nanoparticle. Like a movie star rolling up to a night spot unseen in a blacked-out Bentley, the lipid nanoparticle merges with the host cell’s phospholipid membrane to deliver the mRNA payload, conferring protection against SARS-CoV-2 or its variants. This concept is not new, but the technique has been refined and offers a path forward for the future of therapeutics.

“Lipid nanoparticles and liposome research is a very dynamic field both in industry and academia,” said Philipp Heller, project manager innovation at Evonik Health Care in Darmstadt, Germany. “The field is very open to innovative, new excipients and delivery concepts, and there is a huge space for further R&D. That is what makes it exciting.”


First discovered in the 1960s (, the liposome is composed of lipids with a hydrophilic, phosphoric acid head and a hydrophobic, fatty acid tail. Researchers found that in an aqueous medium, these components formed sheets with the polar heads and fatty acid tails facing in opposite directions. Over time, the fatty acid tails pulled the sheet inward, forming a sphere.

Despite the potential of the liposome, the structures are difficult to produce in large quantities. In addition, the physical stability of the liposome is based on the size, number, and distribution of cavities in the structure.

During the ensuing decades, chemists engineered the next generation of liposome architecture to improve capsule stability and prevent flocculation, coalescing, and fusion. They employed biopolymers, films, and even nanofibers in this feat. Post-processing techniques, like freeze drying and spray drying, also enhance the stability of these microscopic spheres.

An image of Nanolipid

An image of lipid bilayers were discovered
FIG. 1. Closed lipid bilayers were discovered decades ago and have since been manipulated in a variety of ways in order to optimize their drug delivery capabilities. Source: ACS Nano 2021, 15, 16982−17015.

Through these advances, several new liposome structures emerged. In 1991, chemists developed the first lipid nanoparticle ( through processes like film hydration, reverse phase separation, and microfluidic hydrodynamic focusing. Lipid nanoparticle size can be controlled by ultrasonication, extrusion, and microfluidic methods. In the past 30 years, several varieties of lipid nanoparticles emerged.

Solid lipid nanoparticles ( expand on the traditional structure of the liposome by adding new scaffolding that creates additional pockets inside the capsule. These improvements raised the value of the lipid capsules for the pharmaceutical industry. Nanostructured lipid carriers ( have a solid matrix at room temperature that increases the stability for a longer time. This new architecture also expands on delivery options, opening opportunities for injection, as well as routes through the mouth, skin, lungs, and even the eyes to deliver medication. Both solid lipid nanoparticles and nanostructured lipid carriers are made from lipids and stabilizing agents, like surfactants and coating materials. Cubic Liquid Crystalline Nanoparticles, or cubosomes (, round out the liposome evolution. These structures consist of lipids in the cubic phase, which can accommodate proteins better than other lipid-water phases. Cubosomes are highly stable under physiological conditions and can be customized for a specific pore size.


Lipid nanoparticles are composed of a mixture of artificial and natural lipids. They have low toxicity and are biocompatible and biodegradable. Hydrophilic drugs could be transported within the interior of the capsule. Hydrophobic drugs can be embedded within the membrane bilayer

When developing these lipid structures for pharmaceutical purposes, chemists focus on four factors: adsorption, endocytosis, fusion, and lipid exchange. In essence, the lipid nanoparticle must be able to make contact and mesh with the phospholipid bilayer of the host cell membrane, allowing the drug to pass from the liposome to the cell.

With the desire to deliver a drug at the right place and at right time, chemists embedded ligands (e.g., peptides or antibodies) into the membrane that can recognize and bind to specific receptors on the target cell. This approach allows the liposome to deliver drugs to specific cells, opening a new approach for cancer treatment, gene therapy, and molecular imaging. It also has the potential of lowering off-target effects and potentially improving the outcomes for patients. Lipid structures have also been designed to be sensitive to changes in temperature or pH, which behave like triggers to release the drug content.

Liposomes have already been used for a variety of pharmaceutical applications, including Doxil, an antitumor agent used to treat ovarian and metastatic breast cancer, as well as various forms of myeloma. Epaxal, a protein antigen used as a hepatitis vaccine, also benefits from liposomes. Many fungicides use liposomal capsules to transport amphotericin B, a broad-spectrum antibiotic that is particularly effective against the ergosterol-rich fungal membranes. Medical imaging have also used liposomes to transport radiolabels, fluorescent dyes, or quantum dots to specific locations in the body to visualize tumors, obstructions in blood vessels, and other features in the body. Prior to their use in COVID-19 vaccines, nucleic acid drugs have been used to treat viral infection of the retina (cytomegalovirus retinitis) and transthyretin-mediated amyloidosis, a hereditary disease.


Despite their promise, lipid nanoparticles have limitations. Lipid nanoparticles have a very short shelf-life, often less than two years. To prolong viability, most lipid nanoparticles loaded with therapeutics are stored in incredibly cold temperatures (-20°C or colder) to prevent oxidation and hydrolysis. The particles are treated with a cryoprotector to ensure stability of the spheres when reconstituted. Future work is needed to develop new formulations that are viable at normal refrigeration temperatures or even at room temperature.

Loading drugs into the particles can be tricky. Chemists often use a process called active loading to improve how the drug is introduced to the cavities within the structure to ensure the uncharged drug can cross the lipid bilayer without gaining a charge and becoming toxic in the human body. This may be accomplished by trapping the drug in a low pH environment inside the liposome capsule and suspending it in a neutral pH environment (

Once delivered to the body, the lipid nanoparticles are in a race against time to deliver their payload and dodge the body’s immune cells that are actively trying to remove the foreign entity from the body. Studies have found small, charged lipid capsules are more successful at delivering the drug payload. To improve the longevity in the body, chemists have coated the lipid membrane with a polymer, called polyethylene glycol (PEG). This coating puts the liposome in ‘stealth’ mode, allowing it to evade the body’s immune cells, but PEG has also raised concerns of an allergic response that occurs in a small number of people (see sidebar).

Current liposome configurations have a natural affinity for the liver, which means therapeutics, like mRNA, delivered by lipid nanoparticles are predominantly expressed in liver tissue. While this is not a problem, future studies are needed to develop new structures that can deliver pharmaceuticals to a broader range of organs and tissues. According to Heller, Evonik is developing a new polymeric structure that complements current lipid nanoparticle architecture that can work outside of the liver.


The SARS-CoV-2 virus stopped the world in its tracks. The rapid development, testing, and approval of multiple vaccines within one year broke the previous record set by the mumps vaccine, which took four years to develop and approve. The speed with which researchers moved in developing the COVID-19 vaccines was supported by previous investigations into a family of viruses that had been lighting medical fires around the globe for two decades.

An image of mRNA
FIG. 2. mRNA encapsulated with in a lipid nanoparticle. Credit: Evonik Industries AG

SARS-CoV-2 is a member of the coronavirus family, which first raised worldwide concern following the Severe Acute Respiratory Syndrome (SARS) epidemic in 2002. A decade after SARS caught the medical community flat-footed, the Middle East respiratory syndrome (MERS) emerged in 2012. Since this time, researchers have focused on learning about the structure, genome, and life cycle of the family of coronaviruses. In particular, they focused on the importance of the viral spike protein that is integral in how the virus attaches, fuses, and enters the host cell to cause disease. This protein would prove to be the key for several of the COVID-19 vaccines.

With a pandemic bearing down on them, researchers around the world mobilized and began sharing information. Within ten days of the first reported cases in Wuhan, China, researchers had sequenced SARS-CoV-2 and shared this information in an effort of worldwide cooperation. Funding from governmental agencies around the world followed, propelling research efforts forward.

While traditional vaccines use viral proteins or a disabled form of the virus to stimulate a defense by the body, researchers focused on the mRNA of the spike protein. mRNA technology was something researchers had been exploring for some time, and this vaccine would prove its merit. Using a genetic snippet from the spike protein, the vaccine could ‘train’ our bodies to recognize the SARS-CoV-2 virus and prepare to attack and neutralize it. Most vaccines spend years in clinical trials to test their efficacy and safety. Researchers addressed the urgency caused by the pandemic by running clinical trials in parallel, which benefitted from a large number of people who volunteered for the studies. The resulting data proved the safety and efficacy of the vaccines, compelling health departments around the globe to issue emergency use orders while additional studies continued.


Today, many liposome structures, including lipid nanoparticles, are being explored in clinical trials to evaluate the efficacy of different drugs and in other medical applications. Beyond vaccines, mRNA therapies could also be developed for tumor immunotherapy to treat cancer. New therapies are also being developed that use mRNA-loaded lipid nanoparticles to restore normal protein function in patients with a protein deficiency, such as the hereditary disease cystic fibrosis that causes fluids, like mucus, sweat, and digestive juices, to become thick and sticky and block the airway. The pharmaceutical industry is not alone in exploring the benefits of these tiny lipid capsules.

The cosmetics industry is embracing liposomes in new skin treatments that increase skin hydration and treat hyperpigmentation and premature aging ( Lipid nanoparticles have been used in sunscreen formulations to protect skin from adverse elements in the environment and sun damage. Some formulations are also aimed at stimulating cell renewal and wound healing (, and prevent wrinkles. Today, lipid nanoparticles are being explored in new formulations to treat skin conditions, including neurodermatitis and perioral dermatitis, which produce itchy, red, and scaly skin, as well as psoriasis, acne, and rosacea.

In the food industry, lipid nanoparticles open new opportunities to improve solubility, reduce nutrient loss, prolong shelf-life, and improve food quality and safety. Lipid carriers help retain volatile compounds and transport essential oils. These structures also provide a way to improve the bioavailability of supplements. Lipid nanoparticles can be applied using a variety of food industry techniques, including microencapsulation, spray drying, and emulsification.


Despite the careful review during clinical trials and overwhelming success of the COVID-19 vaccines, little is known about the allergic response initiated by the lipid nanoparticle. One study ( examined empty lipid nanoparticle carriers to evaluate how they activate the inflammatory response. The researchers found that the frequency of lipid nanoparticle-stimulating immune response did not differ by age, but one inflammatory pathway (Transformational Growth Factor Beta) was significantly elevated in older adults.

Another study ( examined allergic response associated with the Pfizer/BioNTech vaccine. They found that for every one million people who received this vaccine, 1.1 experienced a severe allergic response (anaphylaxis) ( Both the Pfizer and Moderna vaccines have similar compositions, consisting of ionizable cationic lipid, a PEGylated lipid, cholesterol, and a helper lipid (phospholipid distearoylphosphatidylcholine). The study identified the PEG-lipid component as a likely cause of the allergic response.

PEGylated lipids are a class of polyethylene glycol derivatives. They are added to the liposome to strengthen the structure, extend circulation times, and prevent the particles from aggregating. Previous sensitivity tests have pointed to PEG molecular weight (PEG > 3,350) as a factor in instigating an allergic response, but the vaccines in question used PEG with a molecular weight of 2,000. The study found that the molecular weight may not be the culprit. Instead, it may be the lipid conjugate configuration. The PEG construction in the two vaccines initiate an immune response in a small number of people, resulting in the production of antibodies that led to undesirable side effects. Future approaches could explore new configurations in the shape and structure of PEG in the lipid nanoparticle and find a PEG alternative to reduce an allergic response.

About the Author

Stacy Kish is a science writer for INFORM and other media outlets. She can be contacted at

Attend an AOCS webinar
Sign up for the INFORM TOC
Subscribe to AOCS Smartbrief to stay informed about the latest news