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The Pfizer–BioNTech vaccine against COVID-19 delivers mRNA in lipid nanoparticles. Credit: BioNTech.

Why drug delivery is the key to new medicines

Designing a new drug is not enough; it has to be delivered to its target, which can be achieved via a cornucopia of
vehicles, from nanoparticles and microneedles to red blood cells and microalgae.

Mike May

N
ew drugs are featured daily in University and the Wyss Institute, and his Lipid nanoparticles are essential for
the media, but the method of colleagues in a recent review. effective delivery of mRNA. “Nanoparticles
delivery receives scant attention. A drug and its delivery vehicle must are small enough that they can actually get
A new blockbuster drug can work only if work as a team to accomplish a therapeutic into cells, and the nanoparticles can protect
it is protected and transported to the right objective. “With some of the advanced sensitive molecules that would otherwise
location. Many new approaches to drug delivery systems, it’s about getting the right get destroyed by the body,” such as mRNA,
delivery have been developed recently, and drug to the right part of the body at the right says Robert Langer, Institute Professor at the
others are being tested in clinical trials. New time,” says Nicholas Warne, vice president of Massachusetts Institute of Technology.
methods of drug delivery ultimately aim for pharmaceutical research and development Nanoparticles also help to control the
increased efficacy, as well as improving the at Pfizer. dose. “If you inject a drug directly, it gets
experience for patients — from simplifying into the body at a very high concentration,
the method of taking a drug to improving mRNA’s unsung partner which could cause various types of toxicity,”
its safety. During the ongoing COVID-19 pandemic, Langer explains. “When you put the drug in
“Drug delivery technologies have enabled billions of doses of mRNA vaccines have a nanoparticle, you don’t get that super-high
the development of many pharmaceutical been delivered that use lipid nanoparticles dose.” Instead, the drug is delivered more
products that improve patient health by as the delivery vehicle. mRNA is now rightly slowly, which reduces side effects.
enhancing the delivery of a therapeutic famous as a potential cure for many diseases, Despite the huge benefits of using
to its target site, minimizing off-target and this has generated billions of dollars nanoparticles for drug delivery, there are
accumulation and facilitating patient for Moderna, Pfizer and BioNTech, but the challenges. Langer mentions safety, efficacy
compliance,” wrote Samir Mitragotri, Hiller design of the lipid nanoparticles was just and stability. When a drug is put into a
Professor of Bioengineering at Harvard as important. nanoparticle, the safety of the combination
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Microneedle delivery of medicines that ordinarily

patch wouldn’t be delivered into or across the
Stratum corneum skin,” according to Ryan Donnelly, Chair
Epidemis of Pharmaceutical Technology at Queen’s
University Belfast.
The first patent on microneedles was
Dermis filed in the mid-1970s, but it took until the
1990s for them to be produced in larger
quantities. Microneedles are typically less
An array of hydrogel microneedles sits below a drug reservoir in a microneedle patch. When pressed to
than a millimeter or two tall, are a few
the skin, the microneedles can painlessly deliver a drug into the epidermis. Immune cells, arteries (red),
hundred micrometers across at the base,
veins (blue) and lymphatic vessels (yellow) are shown in the dermis. Credit: Lalitkumar Vora.
and are 10–50 micrometers in diameter at
the tip, and can be made from glass, metals
or polymers. At present, microneedles are
must be determined, as the nanoparticle –70° Celsius and is usable from a refrigerator commercially used only for cosmeceutical
itself could cause side effects. A nanoparticle for about 10 weeks. “It’s not the most stable products, such as Botox, but researchers are
vehicle could also reduce a drug’s efficacy. or convenient,” Warne says. “So, we’re exploring how they could be coated with
Optimization is key, as fixing safety may working on that.” Through technological a drug and then dissolve after penetrating
reduce efficacy, for example. “If you get one improvements, Pfizer and BioNTech have the skin, allowing the drug to enter.
to work well, you might run into a problem already increased stability at 4° C from 5 Alternatively, hollow microneedles could be
on another,” Langer says. days to 1 month. filled with a drug and could release that drug
The lipid nanoparticles in the BNT162b2 by swelling when applied to the skin.
(Pfizer–BioNTech) vaccine against COVID- Organ targeting Until recently, manufacturing was a
19 include a cationic lipid that binds the Lipid nanoparticles have many potential major challenge for microneedles. “It’s one
mRNA, together with cholesterol and uses beyond infectious diseases. As Wei Tao, thing making something on a small scale
phosphocholine, plus a polyethylene glycol a biomaterials researcher at Brigham and by hand in the laboratory, and then there’s
(PEG) lipid for stabilization. “Essentially, Women’s Hospital and Harvard Medical another thing entirely in making millions
we are talking about an emulsion having School, says, “Local delivery of mRNA via of products to high standards that can be
no or very little aqueous space inside the nanoparticles might also hold promise in the reproducibly used by patients, particularly
lipid nanoparticle,” says Steffen Panzner, treatment of malignancies.” in their own home,” Donnelly says. “It’s
vice president of delivery technologies Tao and his colleagues used nanoparticles only in recent years that we have seen a
at BioNTech. That particle is only 70–80 to deliver mRNA to the bladder of mice, number of companies actually working to
nanometers across. targeting the lysine-specific demethylase become manufacturers of microneedles.”
The lipid-nanoparticle technology, KDM6A, a suppressor of bladder cancer. For example, Kindeva in the United
which is in vaccines now used in hundreds But the bladder presents challenges for gene States and Lohmann Therapie-Systeme in
of millions of people, was developed therapy, as any treatments tend to be quickly Germany manufacture microneedle-based
over decades, with the levels of each lipid eliminated in urine. delivery systems.
carefully balanced. Alnylam pioneered the The delivery vehicle developed by Microneedles offer benefits beyond
medical use of lipid nanoparticles with Tao’s team used nanoparticles made from being minimally invasive. A dry drug on
a drug called Onpattro, which delivers poly(lactic-co-glycolic acid), which is a polymeric microneedle array would be
small interfering RNA to treat hereditary biodegradable and is approved by the US temperature stable and easy to apply, making
transthyretin amyloidosis. “As Onpattro Food and Drug Administration. But they it ideal for vaccines against infectious
is repeatedly administered into a patient’s crucially added an outer coating of PEG, diseases in low-income countries. Donnelly
bloodstream, this has really validated the which was molecularly engineered to bind envisions using microneedle arrays for
safety of the new platform,” says Panzner. the mucosal surface, with the hope of sustained delivery of a drug over time,
“This gave us a sufficient overview keeping the mRNA in the bladder longer. which could be useful for people infected
with regards to the safety profile when In studies with mice, the mRNA– with human immunodeficiency virus, who
considering a vaccine that is administered nanoparticle stuck to the bladder and currently take daily pills, or people with
only a few times in small doses into the reduced tumor growth. But without the mental-health conditions, Donnelly notes.
muscle, not in [the] circulation.” PEG coating, urine quickly washed the Nanoparticles can also be combined with
Once the science of lipid nanoparticles nanoparticles away; this showed proof of microneedle technology. “It could be just
was in place, the focus turned to industrial principle and paved the way for studies like a Band-Aid that you could send to the
production. “Making the mRNA is well in humans. developing world for mRNA therapeutics or
established,” Warne says. “People have mRNA vaccines,” Langer explains. In such
been doing that for at least 30 years.” Mass manufacturing microneedles an application, the simplicity of delivering
Getting the RNA in the lipid nanoparticles Scientists have been injecting medications drugs with microneedles and the potential
was also “a pretty simple process, but it has since at least the mid-1600s. Over the stability of such a product could make it
to be done perfectly every time, because centuries, technology has understandably usable around the world.
we’re making billions of doses on an annual improved, with excitement today
basis,” he explains. focused on microneedles. These arrays Cellular delivery
Although the mRNA vaccines against of tiny projections on a solid support are Intravenously injected drugs travel directly
COVID-19 from Moderna and Pfizer– “minimally invasive devices that painlessly into the bloodstream, where they can be
BioNTech have high efficacy, stability and without drawing blood penetrate the quickly cleared by the liver. By comparison,
remains an issue. The vaccine is shipped at skin’s stratum corneum barrier to allow ingested drugs do not get into the

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Plus, the cyanobacterium’s spiral structure

“enables it to be not only more easily trapped
by the intestinal villi but also adhered to
the intestinal wall, thereby prolonging the
retention time of the drugs in the intestine,”
says Tao.
Drug delivery via cyanobacteria has
already shown promise. In a mouse model
of acute colitis, using S. platensis to deliver
curcumin reduced “the production of
proinflammatory cytokines and thereby
exerted anti-inflammatory effects against
colitis,” Tao says. “Our technology may
offer safe and innovative means of oral drug
administration with clinical potential against
various intestinal diseases.”

Squeeze to deliver
When cells are used as drug-delivery
vehicles, the cell must be ‘persuaded’ to
Polymer nanoparticles are attached to red blood cells for targeted delivery. The nanoparticles carry the drug, either on its surface or inside
shear off into the target organ when the red blood cells pass through the organ’s capillaries.
it. Scientists use many methods, such as
Credit: Samir Mitragotri.
electricity, to get drugs into cells, but Armon
Sharei stumbled across an unexpected
approach while working on his PhD at the
bloodstream as quickly. “We are overcoming to reach its target. “Some therapeutics, Massachusetts Institute of Technology.
this hurdle by using red blood cells as a especially the hydrophobic ones, can be Sharei found that pushing cells through a
carrier,” Mitragotri says. “We reversibly easily blocked by the mucus and thus constriction — thereby squeezing them —
attach therapies to the surface of red blood [are] quickly removed before they can be causes transient holes to appear in the outer
cells, which shields them from clearance in absorbed by the intestine,” says Tao. membrane, which can let in a potential
the liver.” If the intestine is the ultimate target treatment, with the cell membrane resealing
Drugs carried by erythrocytes, or red for the drug, then there is the opposite afterwards. Sharei spun out this method
blood cells, can more easily target tissues. challenge: to avoid crossing the mucus into SQZBIOTECH, where he is the founder
Mitragotri’s team is using this method to membrane and stay in the intestine for as and CEO. SQZBIOTECH already has cell
deliver a variety of therapies, including long as possible. “It is also important to therapies for autoimmune and infectious
small molecules, biologics and mRNA. increase the intestinal retention time of the diseases, such as infection with human
After incorporating the therapeutic with a drugs, especially in treating different types papillomavirus, as well as various cancers, in
nanoparticle, the scientists mix that with the of intestinal cancers, to reduce the dose or pre-clinical and clinical testing.
erythrocytes. Some of the nanoparticles stick duration of drug administration and reduce Langer, who was one of Sharei’s PhD
to the outside of the cells, but it is not clear side effects,” Tao says. advisors, says, “This was just very unusual.”
why. It is not a covalent bond, but it could Tao is taking on those challenges in He adds, “You could put almost anything
be caused by electrostatic or hydrophobic intestinal-disease treatments by delivering in the cell, and you can do literally billions
interactions, or something else. drugs such as curcumin, a component of of cells a minute.” It is both surprising and
“This is an orthogonal approach for turmeric, with the edible cyanobacterium novel. As Langer says, “I’ve not seen anything
tissue targeting [that] makes use of the Spirulina platensis, a common dietary like it and certainly didn’t expect it.”
body’s own cells to deliver drugs,” Mitragotri supplement. By simply dissolving curcumin Perhaps the most exciting advances
says. “That’s what makes it interesting.” in ethanol, diluting it with water, adding that in drug delivery will arise from other
Orally administered medications are to a suspension on S. platensis, and stirring unexpected mechanisms. “That’s how
usually the most convenient for a patient, the mixture for 12 hours, he ensures that the science works,” Langer says. “Sometimes,
but this route requires that the drug make bacteria’s surface takes up the drug. you make serendipitous discoveries.” ❐
its way through the acidic conditions in Tao says, “Drug carriers based on
the stomach. Stomach acid will denature or Spirulina platensis possess the properties Mike May
degrade many drugs, including those based of easy quantity production and excellent Freelance writer and editor, Bradenton, FL, USA.
on nucleic acids or proteins, and even if biocompatibility without safety concerns.” In
a drug survives the stomach, it must then 2011, US Pharmacopeia gave this bacterium Published online: 6 June 2022
cross the mucus barrier in the intestines a high safety rating for human consumption. https://doi.org/10.1038/s41591-022-01826-y

1102 Nature Medicine | VOL 28 | June 2022 | 1100–1102 | www.nature.com/naturemedicine