Lipid-based nanoparticle

Based on Wikipedia: Lipid-based nanoparticle

In December 2020, a nurse in New York became the first American to receive a COVID-19 vaccine outside of clinical trials. The injection she received contained messenger RNA—genetic instructions telling her cells to build a harmless piece of the coronavirus spike protein. But the truly remarkable part wasn't the RNA itself. It was the tiny fat bubbles carrying it.

Those bubbles, called lipid nanoparticles, solved a problem that had plagued scientists for decades: how do you get fragile genetic material into human cells without it falling apart?

The Problem with Naked RNA

Messenger RNA is astonishingly delicate. Left unprotected, it degrades within minutes. Your body is full of enzymes specifically designed to chew up stray RNA—a defense mechanism against viruses that backfires when you're trying to deliver medicine.

Even if RNA somehow survived the journey through your bloodstream, it would face another obstacle. Cell membranes are made of lipids—fats—and they're designed to keep things out. RNA carries a negative electrical charge. Lipids also carry a negative charge. Like magnets with the same pole facing each other, they repel.

So scientists needed a delivery vehicle. Something that could protect RNA from degradation, sneak past the immune system, and slip through cell membranes to deliver its payload. The solution turned out to be hiding in plain sight: use the cell membrane's own building blocks against it.

What Exactly Is a Lipid Nanoparticle?

Picture a sphere roughly one-thousandth the width of a human hair. That's a lipid nanoparticle—typically between 10 and 1000 nanometers across. To give you a sense of scale: if a lipid nanoparticle were the size of a basketball, a red blood cell would be a two-story house.

These tiny spheres are assembled from four key ingredients, each with a specific job.

First, phospholipids. These are the same molecules that make up your cell membranes—two fatty tails attached to a phosphate head. They give the nanoparticle its basic structure, arranging themselves into a shell that mimics natural biological barriers.

Second, cholesterol. Yes, the same cholesterol your doctor measures in blood tests. Here it serves as a structural reinforcement, making the particle more stable and rigid. Without it, the sphere would be too floppy to survive the journey through your body.

Third, polyethylene glycol-derived lipids—called "PEGylated lipids" for short. Polyethylene glycol is a compound you might recognize from everyday products like toothpaste and laxatives. When attached to lipids, it creates a kind of stealth coating. The PEG chains stick out from the particle's surface like tiny hairs, preventing the immune system from recognizing the particle as foreign and destroying it before it reaches its target.

Fourth, and most crucially: ionizable lipids. This is where the real magic happens.

The Ionizable Lipid Breakthrough

Remember the electrical charge problem? RNA is negative. Regular lipids are negative. They won't mix.

In the mid-1980s, a scientist named Philip Felgner at Syntex came up with an initial solution: artificially create lipids with a positive charge. Positive meets negative, they attract, problem solved. His cationic lipids—"cationic" meaning positively charged—could indeed bind to RNA and carry it into cells.

But there was a catch. By the late 1990s, researchers discovered that permanently positive lipids damaged cell membranes. They were too aggressive, causing toxic side effects that made them unsuitable for medical use.

The breakthrough came from Pieter Cullis at the University of British Columbia. He developed ionizable cationic lipids—lipids whose charge changes depending on their environment.

Here's the clever part. When you're mixing ingredients in the laboratory, you keep the solution acidic. At low pH, these ionizable lipids become positively charged, allowing them to grab onto the negatively charged RNA. But once the nanoparticles enter your bloodstream—which has a neutral pH around 7.4—the lipids become neutral. No charge, no membrane damage, no toxicity.

Then comes the final act. When the nanoparticle gets swallowed by a cell through a process called endocytosis, it ends up trapped in a small compartment called an endosome. Endosomes are acidic. The low pH flips the ionizable lipids positive again, allowing the nanoparticle to break free from the endosome and release its RNA cargo into the cell's interior.

It's a molecular Trojan horse with a pH-sensitive lock.

The Road from Laboratory to Pharmacy

The first drug to use lipid nanoparticle delivery wasn't a vaccine. It was a treatment for a rare genetic disease.

In 2018, the United States Food and Drug Administration approved Onpattro—generic name patisiran—for treating hereditary transthyretin amyloidosis. This condition causes misfolded proteins to accumulate in organs, leading to nerve damage and heart failure. Onpattro uses small interfering RNA (siRNA) packaged in lipid nanoparticles to silence the gene producing these harmful proteins.

Small interfering RNA and messenger RNA are cousins in the nucleic acid family, but they work differently. siRNA is short—typically 20 to 25 base pairs—and its job is to silence genes by destroying specific messenger RNA before it can be translated into protein. Messenger RNA, by contrast, carries instructions for building proteins.

The lipid nanoparticles developed for siRNA became the foundation for mRNA delivery, but adaptation wasn't straightforward. mRNA molecules are much longer than siRNA—thousands of base pairs versus a couple dozen. The ionizable lipids that worked well for short siRNA strands weren't optimal for much longer mRNA.

This prompted intensive research during the mid-2010s into novel ionizable lipids specifically designed for mRNA. Moderna developed a proprietary lipid called SM-102. Meanwhile, Acuitas Therapeutics—a company co-founded by Pieter Cullis to commercialize his LNP research—developed ALC-0315, which they licensed to Pfizer and BioNTech.

When SARS-CoV-2 emerged in late 2019, this decade of groundwork meant that mRNA vaccine technology was ready. The lipid nanoparticle delivery system was no longer experimental—it was proven, scalable, and understood well enough to deploy at pandemic speed.

Solid Lipid Nanoparticles: A Different Architecture

The lipid nanoparticles in COVID vaccines are one member of a larger family. Their cousins—solid lipid nanoparticles, abbreviated SLNs—take a different approach to the same problem.

Where standard lipid nanoparticles have a fluid interior, solid lipid nanoparticles have exactly what their name suggests: a solid core. Think of the difference between a water balloon and a bouncy ball. Both are spherical, both can carry things inside them, but their internal consistency is fundamentally different.

The solid core is typically made from fats that remain solid at body temperature: triglycerides like tristearin, fatty acids like stearic acid, or waxes like cetyl palmitate. Surfactants—molecules that reduce surface tension, the same principle that makes soap work—coat the outside to keep the particles from clumping together.

Why go solid? Several reasons.

First, controlled release. A solid matrix holds onto drug molecules more tightly than a liquid one. As the particle slowly erodes or the drug gradually diffuses out, you get sustained delivery over time rather than a single burst.

Second, stability. Solid particles don't merge together as easily as liquid droplets. They can survive storage and transport conditions that would destroy more fragile formulations.

Third, versatility. Despite having a lipid—meaning fat-loving—core, solid lipid nanoparticles can actually carry both fat-soluble and water-soluble drugs. The trick is in how you load them: water-soluble molecules can be trapped in tiny pockets within the solid matrix.

A recent example: researchers loaded solid lipid nanoparticles with ferrous sulfate—a form of iron—for oral delivery. Iron supplements are notoriously hard on the stomach, causing nausea and constipation. Encapsulating the iron in lipid nanoparticles could potentially reduce these side effects while improving absorption.

Nanostructured Lipid Carriers: The Best of Both Worlds

If solid lipid nanoparticles have a completely solid core and standard lipid nanoparticles have a fluid core, nanostructured lipid carriers split the difference.

These particles contain a mixture of solid and liquid lipids in their center. The result is an imperfect, irregular internal structure—and that imperfection is actually the point.

Think of packing a suitcase. If you fold everything perfectly into rigid stacks, you can't fit much. But if you have some flexible items you can squeeze into gaps and crevices, suddenly you have room for more. The same principle applies here: the disordered structure created by mixing solid and liquid lipids leaves more space for drug molecules.

Nanostructured lipid carriers can typically hold more drug than solid lipid nanoparticles of the same size. They also offer better control over drug release, since you can tune the solid-to-liquid ratio to achieve the delivery profile you want.

Making Nanoparticles at Scale

Laboratory demonstrations are one thing. Manufacturing billions of doses is another.

Several methods exist for creating lipid nanoparticles, each with tradeoffs.

High-shear homogenization forces the lipid mixture through a tiny gap at enormous pressure. The shearing forces break the mixture into nanoscale droplets. It's relatively straightforward to scale up—the pharmaceutical industry has been using high-pressure homogenizers for decades—but controlling particle size precisely can be challenging.

Ultrasonication uses sound waves to accomplish something similar. High-frequency vibrations create microscopic bubbles that violently collapse, fragmenting the lipids into nanoparticles. This method can produce very small, uniform particles—down to 30 nanometers—but requires long sonication times that may not be practical for large-scale production.

Solvent emulsification dissolves lipids in an organic solvent, mixes them with water, then evaporates the solvent away. The lipids, suddenly finding themselves in an aqueous environment they can't dissolve in, spontaneously assemble into nanoparticles. This approach avoids the heat generated by other methods—useful when your drug is temperature-sensitive—but introduces the complication of removing all traces of organic solvent from the final product.

Whatever method you use, quality control is essential. Every batch must be tested for particle size (too big and they won't enter cells; too small and they might be cleared too quickly by the kidneys), polydispersity (how uniform the particles are), drug loading efficiency (how much cargo actually ended up inside), and endotoxin levels (bacterial contaminants that cause fever and inflammation).

Beyond Vaccines: The Future of Lipid Nanoparticle Delivery

COVID vaccines demonstrated what lipid nanoparticles can do. Researchers are now exploring what else they might deliver.

Ocular drug delivery is one promising area. Getting drugs into the eye is surprisingly difficult. Most eye drops wash away within minutes, and the cornea presents a formidable barrier. Solid lipid nanoparticles enhance corneal absorption and can improve the bioavailability of both water-soluble and fat-soluble drugs. As a bonus, they can be sterilized by autoclaving—steam under pressure—which is required for any preparation that goes into the eye.

Oral drug delivery presents different challenges. Many promising drug molecules are poorly absorbed from the gut, either because they're not soluble in water or because they're broken down before they can reach the bloodstream. Lipid nanoparticles can protect these molecules and enhance their absorption, partly by exploiting the lymphatic system—the network of vessels that normally absorbs dietary fats.

This lymphatic route is particularly interesting. When you eat a fatty meal, specialized cells in your intestines package the fats into particles called chylomicrons, which enter the lymphatic system before eventually reaching the bloodstream. Lipid nanoparticles can hitch a ride on this same pathway, bypassing the liver's first-pass metabolism that destroys many oral drugs before they can take effect.

Cancer treatment is another frontier. Tumors have leaky blood vessels and poor lymphatic drainage—a combination that causes nanoparticles to accumulate preferentially in tumor tissue. Researchers are exploring lipid nanoparticles decorated with targeting molecules that could deliver chemotherapy directly to cancer cells while sparing healthy tissue.

The Broader Family of Lipid-Based Delivery Systems

Lipid nanoparticles are part of an ecosystem of lipid-based drug delivery technologies, each with its own strengths.

Liposomes, the grandparent of the family, were developed in the 1960s. They're hollow spheres with a lipid bilayer shell—imagine a tiny soap bubble made of the same material as cell membranes. The hollow interior can carry water-soluble drugs. Several liposomal drugs are already on the market, including Doxil (liposomal doxorubicin for cancer) and AmBisome (liposomal amphotericin B for fungal infections).

But liposomes have limitations. Their hollow structure limits how much drug they can carry. They can be unstable, fusing together or leaking their contents over time. And they struggled with nucleic acid delivery—the very application where lipid nanoparticles excel.

Micelles are simpler structures: single-layer spheres with lipid tails pointing inward and heads pointing outward. They're good for solubilizing fat-soluble drugs but can't carry water-soluble cargo.

Lipoplexes are complexes of DNA or RNA with cationic lipids—essentially the first-generation technology that preceded today's ionizable lipid nanoparticles. They work but carry the toxicity issues that ionizable lipids were designed to avoid.

Each technology occupies its own niche. Lipid nanoparticles happened to be the right solution for the right problem at the right time—delivering mRNA vaccines during a pandemic.

A Platform Technology Comes of Age

The term "platform technology" gets thrown around a lot in biotech. It means a foundational technology that can be adapted for many different applications. Lipid nanoparticles genuinely deserve the label.

The same basic architecture—ionizable lipids, phospholipids, cholesterol, PEGylated lipids—can deliver siRNA, mRNA, or potentially other nucleic acids. Change the RNA sequence, and you change what the therapy does. The delivery system stays the same.

This modularity explains how Moderna and BioNTech/Pfizer developed COVID vaccines in record time. They weren't starting from scratch. They were adapting a delivery system that had been refined over decades for a new payload. Once they had the mRNA sequence encoding the spike protein—which was published in January 2020, mere weeks after the virus was identified—they could slot it into their existing lipid nanoparticle platform.

The next pandemic, if it comes, will likely see even faster vaccine development. The lipid nanoparticle delivery system is now proven at scale. The manufacturing infrastructure exists. The regulatory pathway is established. All that's needed is the right sequence.

Beyond pandemics, the same platform could enable personalized cancer vaccines—mRNA encoding tumor-specific mutations, packaged in lipid nanoparticles, teaching each patient's immune system to attack their specific cancer. Gene therapies that were once science fiction are becoming clinical reality.

None of this would be possible without those tiny fat bubbles. Lipid nanoparticles are the unsung heroes of the mRNA revolution—a triumph of pharmaceutical engineering hiding in plain sight.