‘Nanotraps’ are not vaccines although they do call the immune system into play. They represent a different way for dealing with COVID-19. (This work reminds of my June 24, 2020 posting Tiny sponges lure coronavirus away from lung cells where the researchers have a similar approach with what they call ‘nanosponges’.)
Researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have designed a completely novel potential treatment for COVID-19: nanoparticles that capture SARS-CoV-2 viruses within the body and then use the body’s own immune system to destroy it.
These “Nanotraps” attract the virus by mimicking the target cells the virus infects. When the virus binds to the Nanotraps, the traps then sequester the virus from other cells and target it for destruction by the immune system.
In theory, these Nanotraps could also be used on variants of the virus, leading to a potential new way to inhibit the virus going forward. Though the therapy remains in early stages of testing, the researchers envision it could be administered via a nasal spray as a treatment for COVID-19.
“Since the pandemic began, our research team has been developing this new way to treat COVID-19,” said Asst. Prof. Jun Huang, whose lab led the research. “We have done rigorous testing to prove that these Nanotraps work, and we are excited about their potential.”
Designing the perfect trap
To design the Nanotrap, the research team – led by postdoctoral scholar Min Chen and graduate student Jill Rosenberg – looked into the mechanism SARS-CoV-2 uses to bind to cells: a spike-like protein on its surface that binds to a human cell’s ACE2 receptor protein.
To create a trap that would bind to the virus in the same way, they designed nanoparticles with a high density of ACE2 proteins on their surface. Similarly, they designed other nanoparticles with neutralizing antibodies on their surfaces. (These antibodies are created inside the body when someone is infected and are designed to latch onto the coronavirus in various ways).
Both ACE2 proteins and neutralizing antibodies have been used in treatments for COVID-19, but by attaching them to nanoparticles, the researchers created an even more robust system for trapping and eliminating the virus.
Made of FDA [US Food and Drug Administration]-approved polymers and phospholipids, the nanoparticles are about 500 nanometers in diameter – much smaller than a cell. That means the Nanotraps can reach more areas inside the body and more effectively trap the virus.
The researchers tested the safety of the system in a mouse model and found no toxicity. They then tested the Nanotraps against a pseudovirus – a less potent model of a virus that doesn’t replicate – in human lung cells in tissue culture plates and found that they completely blocked entry into the cells.
Once the pseudovirus bound itself to the nanoparticle – which in tests took about 10 minutes after injection – the nanoparticles used a molecule that calls the body’s macrophages to engulf and degrade the Nanotrap. Macrophages will generally eat nanoparticles within the body, but the Nanotrap molecule speeds up the process. The nanoparticles were cleared and degraded within 48 hours.
The researchers also tested the nanoparticles with a pseudovirus in an ex vivo lung perfusion system – a pair of donated lungs that is kept alive with a ventilator – and found that they completely blocked infection in the lungs.
They also collaborated with researchers at Argonne National Laboratory to test the Nanotraps with a live virus (rather than a pseudovirus) in an in vitro system. They found that their system inhibited the virus 10 times better than neutralizing antibodies or soluble ACE2 alone.
A potential future treatment for COVID-19 and beyond
Next the researchers hope to further test the system, including more tests with a live virus and on the many virus variants.
“That’s what is so powerful about this Nanotrap,” Rosenberg said. “It’s easily modulated. We can switch out different antibodies or proteins or target different immune cells, based on what we need with new variants.”
The Nanotraps can be stored in a standard freezer and could ultimately be given via an intranasal spray, which would place them directly in the respiratory system and make them most effective.
The researchers say it is also possible to serve as a vaccine by optimizing the Nanotrap formulation, creating an ultimate therapeutic system for the virus.
“This is the starting point,” Huang said. “We want to do something to help the world.”
The research involved collaborators across departments, including chemistry, biology, and medicine.
Here’s a link to and a citation for the paper,
Nanotraps for the containment and clearance of SARS-CoV-2 by Min Chen, Jillian Rosenberg, Xiaolei Cai, Andy Chao Hsuan Lee, Jiuyun Shi, Mindy Nguyen, Thirushan Wignakumar, Vikranth Mirle, Arianna Joy Edobor, John Fung, Jessica Scott Donington, Kumaran Shanmugarajah, Yiliang Lin, Eugene Chang, Glenn Randall, Pablo Penaloza-MacMaster, Bozhi Tian, Maria Lucia Madariaga, Jun Huang. Matter, April 19, 2021, DOI: https://doi.org/10.1016/j.matt.2021.04.005
A year later i still don’t know what came over me but I got the idea that I could write a 10-year (2010 – 2019) review of science culture in Canada during the last few days of 2019. Somehow two and half months later, I managed to publish my 25,000+ multi-part series.
COVID-19 was mentioned and featured here a number of times throughout the year. I’m highlighting two of those postings. The first is a June 24, 2020 posting titled, Tiny sponges lure coronavirus away from lung cells. It’s a therapeutic approach that is not a vaccine but a way of neutralizing the virus. The idea is that the nanosponge is coated in the material that the virus seeks in a human cell. Once the virus locks onto the sponge, it is unable to seek out cells. If I remember rightly, the sponges along with the virus are disposed of by the body’s usual processes.
The second COVID-19 posting I’m highlighting is my first ever accepted editorial opinion by the Canadian Science Policy Centre (CSPC). I republished the piece here in a May 15, 2020 posting, which included all of my references. However, the magazine version is more attractively displayed in the CSPC Featured Editorial Series Volume 1, Issue 2, May 2020 PDF on pp. 31-2.
Artist Joseph Nechvatal reached out to me earlier this year regarding his viral symphOny (2006-2008), a 1 hour 40 minute collaborative electronic noise music symphony. It was featured in an April 7, 2020 posting which seemed strangely à propos during a pandemic even though the work was focused on viral artificial life. You can access it for free https://archive.org/details/ViralSymphony but the Internet Archive where this is stored is requesting donations.
Also on a vaguely related COVID-19 note, there’s my December 7, 2020 posting titled, Digital aromas? And a potpourri of ‘scents and sensibility’. As any regular readers may know, I have a longstanding interest in scent and fragrances. The COVID-19 part of the posting (it’s not about losing your sense of smell) is in the subsection titled, Smelling like an old book. Apparently some folks are missing the smell of bookstores and Powell’s books have responded to that need with a new fragrance.
For anyone who may have missed it, I wrote an update of the CRISPR twin affair in my July 28, 2020 posting, titled, July 2020 update on Dr. He Jiankui (the CRISPR twins) situation.
Finishing off with 2020, I wrote a commentary (mostly focused on the Canada chapter) about a book titled, Communicating Science: A Global Perspective in my December 10, 2020 posting. The book offers science communication perspectives from 39 different countries.
I have no doubt there will be delights ahead but as they are in the realm of discovery and, at this point, they are currently unknown.
My future plans include a posting about trust and governance. This has come about since writing my Dec. 29, 2020 posting titled, “Governments need to tell us when and how they’re using AI (artificial intelligence) algorithms to make decisions” and stumbling across a reference to a December 15, 2020 article by Dr. Andrew Maynard titled, Why Trustworthiness Matters in Building Global Futures. Maynard’s focus was on a newly published report titled, Trust & Tech Governance.
I will also be considering the problematic aspects of science communication and my own shortcomings. On the heels of reading more than usually forthright discussions of racism in Canada across multiple media platforms, I was horrified to discover I had featured, without any caveats, work by a man who was deeply problematic with regard to his beliefs about race. He was a eugenicist, as well as, a zoologist, naturalist, philosopher, physician, professor, marine biologist, and artist who coined many terms in biology, including ecology, phylum, phylogeny, and Protista; see his Wikipedia entry.
A Dec. 23, 2020 news release on EurekAlert (Scientists at Tel Aviv University develop new gene therapy for deafness) and a December 2020 article by Sarah Zhang for The Atlantic about prenatal testing and who gets born have me wanting to further explore the field of how genetic testing and therapies will affect our concepts of ‘normality’. Fingers crossed I’ll be able to get Dr. Gregor Wolbring to answer a few questions for publication here. (Gregor is a tenured associate professor [in Alberta, Canada] at the University of Calgary’s Cumming School of Medicine and a scholar in the field of ‘ableism’. He is deeply knowledgeable about notions of ability vs disability.)
As 2021 looms, I’m hopeful that I’ll be featuring more art/sci (or sciart) postings, which is my segue to a more hopeful note about 2021 will bring us,
It’s an apple! This is one of the many images embedded in Annie Ewbank’s January 6, 2020 article about rare and beautiful apples for Atlas Obscura (featured on getpocket.com),
In early 2020, inside a bright Brooklyn gallery that is plastered in photographs of apples, William Mullan is being besieged with questions.
A writer is researching apples for his novel set in post-World War II New York. An employee of a fruit-delivery company, who covetously eyes the round table on which Mullan has artfully arranged apples, asks where to buy his artwork.
But these aren’t your Granny Smith’s apples. A handful of Knobbed Russets slumping on the table resemble rotting masses. Despite their brown, wrinkly folds, they’re ripe, with clean white interiors. Another, the small Roberts Crab, when sliced by Mullan through the middle to show its vermillion flesh, looks less like an apple than a Bing cherry. The entire lineup consists of apples assembled by Mullan, who, by publishing his fruit photographs in a book and on Instagram, is putting the glorious diversity of apples in the limelight.
Scientists are working overtime to find an effective treatment for COVID-19, the illness caused by the new coronavirus, SARS-CoV-2. Many of these efforts target a specific part of the virus, such as the spike protein. Now, researchers reporting in Nano Letters have taken a different approach, using nanosponges coated with human cell membranes –– the natural targets of the virus –– to soak up SARS-CoV-2 and keep it from infecting cells in a petri dish.
To gain entry, SARS-CoV-2 uses its spike protein to bind to two known proteins on human cells, called ACE2 and CD147. Blocking these interactions would keep the virus from infecting cells, so many researchers are trying to identify drugs directed against the spike protein. Anthony Griffiths, Liangfang Zhang and colleagues had a different idea: making a nanoparticle decoy with the virus’ natural targets, including ACE2 and CD147, to lure SARS-CoV-2 away from cells. And to test this idea, they conducted experiments with the actual SARS-CoV-2 virus in a biosafety level 4 lab.
The researchers coated a nanoparticle polymer core with cell membranes from either human lung epithelial cells or macrophages –– two cell types infected by SARS-CoV-2. They showed that the nanosponges had ACE2 and CD147, as well as other cell membrane proteins, projecting outward from the polymer core. When administered to mice, the nanosponges did not show any short-term toxicity. Then, the researchers treated cells in a dish with SARS-CoV-2 and the lung epithelial or macrophage nanosponges. Both decoys neutralized SARS-CoV-2 and prevented it from infecting cells to a similar extent. The researchers plan to next test the nanosponges in animals before moving to human clinical trials. In theory, the nanosponge approach would work even if SARS-CoV-2 mutates to resist other therapies, and it could be used against other viruses, as well, the researchers say.
There are two research teams involved, one at Boston University and the other at the University of California at San Diego (UC San Diego or UCSD). The June 18, 2020 Boston University news release (also on EurekAlert) by Kat J. McAlpine adds more details about the research, provides some insights from the researchers, and is a little redundant if you’ve already seen the ACS news release,
Imagine if scientists could stop the coronavirus infection in its tracks simply by diverting its attention away from living lung cells? A new therapeutic countermeasure, announced in a Nano Letters study by researchers from Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and the University of California San Diego, appears to do just that in experiments that were carried out at the NEIDL in Boston.
“I was skeptical at the beginning because it seemed too good to be true,” says NEIDL microbiologist Anna Honko, one of the co-first authors on the study. “But when I saw the first set of results in the lab, I was just astonished.”
The technology consists of very small, nanosized drops of polymers–essentially, soft biofriendly plastics–covered in fragments of living lung cell and immune cell membranes.
“It looks like a nanoparticle coated in pieces of cell membrane,” Honko says. “The small polymer [droplet] mimics a cell having a membrane around it.”
The SARS-CoV-2 virus seeks out unique signatures of lung cell membranes and latches onto them. When that happens inside the human body, the coronavirus infection takes hold, with the SARS-CoV-2 viruses hijacking lung cells to replicate their own genetic material. But in experiments at the NEIDL, BU researchers observed that polymer droplets laden with pieces of lung cell membrane did a better job of attracting the SARS-CoV-2 virus than living lung cells. [emphasis mine]
By fusing with the SARS-CoV-2 virus better than living cells can, the nanotechnology appears to be an effective countermeasure to coronavirus infection, preventing SARS-CoV-2 from attacking cells.
“Our guess is that it acts like a decoy, it competes with cells for the virus,” says NEIDL microbiologist Anthony Griffiths, co-corresponding author on the study. “They are little bits of plastic, just containing the outer pieces of cells with none of the internal cellular machinery contained inside living cells. Conceptually, it’s such a simple idea. It mops up the virus like a sponge.”
That attribute is why the UC San Diego and BU research team call the technology “nanosponges.” Once SARS-CoV-2 binds with the cell fragments inside a nanosponge droplet–each one a thousand times smaller than the width of a human hair–the coronavirus dies. Although the initial results are based on experiments conducted in cell culture dishes, the researchers believe that inside a human body, the biodegradable nanosponges and the SARS-CoV-2 virus trapped inside them could then be disposed of by the body’s immune system. The immune system routinely breaks down and gets rid of dead cell fragments caused by infection or normal cell life cycles.
There is also another important effect that the nanosponges have in the context of coronavirus infection. Honko says nanosponges containing fragments of immune cells can soak up cellular signals that increase inflammation [emphases mine]. Acute respiratory distress, caused by an inflammatory cascade inside the lungs, is the most deadly aspect of the coronavirus infection, sending patients into the intensive care unit for oxygen or ventilator support to help them breathe.
But the nanosponges, which can attract the inflammatory molecules that send the immune system into dangerous overdrive, can help tamp down that response, Honko says. By using both kinds of nanosponges, some containing lung cell fragments and some containing pieces of immune cells, she says it’s possible to “attack the coronavirus and the [body’s] response” responsible for disease and eventual lung failure.
At the NEIDL, Honko and Griffiths are now planning additional experiments to see how well the nanosponges can prevent coronavirus infection in animal models of the disease. They plan to work closely with the team of engineers at UC San Diego, who first developed the nanosponges more than a decade ago, to tailor the technology for eventual safe and effective use in humans.
“Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets,” said Liangfang Zhang, a UC San Diego nanoengineer and leader of the California-based team, according to a UC San Diego press release. “Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys.”
When the novel coronavirus first appeared, the idea of using the nanosponges to combat the infection came to Zhang almost immediately. He reached out to the NEIDL for help. Looking ahead, the BU and UC San Diego collaborators believe the nanosponges can easily be converted into a noninvasive treatment.
“We should be able to drop it right into the nose,” Griffiths says. “In humans, it could be something like a nasal spray.”
Honko agrees: “That would be an easy and safe administration method that should target the appropriate [respiratory] tissues. And if you wanted to treat patients that are already intubated, you could deliver it straight into the lung.”
Griffiths and Honko are especially intrigued by the nanosponges as a new platform for treating all types of viral infections. “The broad spectrum aspect of this is exceptionally appealing,” Griffiths says. The researchers say the nanosponge could be easily adapted to house other types of cell membranes preferred by other viruses, creating many new opportunities to use the technology against other tough-to-treat infections like the flu and even deadly hemorrhagic fevers caused by Ebola, Marburg, or Lassa viruses.
“I’m interested in seeing how far we can push this technology,” Honko says.
The University of California at* San Diego has released a video illustrating the nanosponges work,
Nanoparticles cloaked in human lung cell membranes and human immune cell membranes can attract and neutralize the SARS-CoV-2 virus in cell culture, causing the virus to lose its ability to hijack host cells and reproduce.
The first data describing this new direction for fighting COVID-19 were published on June 17 in the journal Nano Letters. The “nanosponges” were developed by engineers at the University of California San Diego and tested by researchers at Boston University.
The UC San Diego researchers call their nano-scale particles “nanosponges” because they soak up harmful pathogens and toxins.
In lab experiments, both the lung cell and immune cell types of nanosponges caused the SARS-CoV-2 virus to lose nearly 90% of its “viral infectivity” in a dose-dependent manner. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.
Instead of targeting the virus itself, these nanosponges are designed to protect the healthy cells the virus invades.
“Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets. Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys,” said Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering.
His lab first created this biomimetic nanosponge platform more than a decade ago and has been developing it for a wide range of applications ever since [emphasis mine]. When the novel coronavirus appeared, the idea of using the nanosponge platform to fight it came to Zhang “almost immediately,” he said.
In addition to the encouraging data on neutralizing the virus in cell culture, the researchers note that nanosponges cloaked with fragments of the outer membranes of macrophages could have an added benefit: soaking up inflammatory cytokine proteins, which are implicated in some of the most dangerous aspects of COVID-19 and are driven by immune response to the infection.
Making and testing COVID-19 nanosponges
Each COVID-19 nanosponge–a thousand times smaller than the width of a human hair–consists of a polymer core coated in cell membranes extracted from either lung epithelial type II cells or macrophage cells. The membranes cover the sponges with all the same protein receptors as the cells they impersonate–and this inherently includes whatever receptors SARS-CoV-2 uses to enter cells in the body.
The researchers prepared several different concentrations of nanosponges in solution to test against the novel coronavirus. To test the ability of the nanosponges to block SARS-CoV-2 infectivity, the UC San Diego researchers turned to a team at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) to perform independent tests. In this BSL-4 lab–the highest biosafety level for a research facility–the researchers, led by Anthony Griffiths, associate professor of microbiology at Boston University School of Medicine, tested the ability of various concentrations of each nanosponge type to reduce the infectivity of live SARS-CoV-2 virus–the same strains that are being tested in other COVID-19 therapeutic and vaccine research.
At a concentration of 5 milligrams per milliliter, the lung cell membrane-cloaked sponges inhibited 93% of the viral infectivity of SARS-CoV-2. The macrophage-cloaked sponges inhibited 88% of the viral infectivity of SARS-CoV-2. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.
“From the perspective of an immunologist and virologist, the nanosponge platform was immediately appealing as a potential antiviral because of its ability to work against viruses of any kind. This means that as opposed to a drug or antibody that might very specifically block SARS-CoV-2 infection or replication, these cell membrane nanosponges might function in a more holistic manner in treating a broad spectrum of viral infectious diseases. I was optimistically skeptical initially that it would work, and then thrilled once I saw the results and it sunk in what this could mean for therapeutic development as a whole,” said Anna Honko, a co-first author on the paper and a Research Associate Professor, Microbiology at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL).
In the next few months, the UC San Diego researchers and collaborators will evaluate the nanosponges’ efficacy in animal models. The UC San Diego team has already shown short-term safety in the respiratory tracts and lungs of mice. If and when these COVID-19 nanosponges will be tested in humans depends on a variety of factors, but the researchers are moving as fast as possible.
“Another interesting aspect of our approach is that even as SARS-CoV-2 mutates, as long as the virus can still invade the cells we are mimicking, our nanosponge approach should still work. I’m not sure this can be said for some of the vaccines and therapeutics that are currently being developed,” said Zhang.
The researchers also expect these nanosponges would work against any new coronavirus or even other respiratory viruses, including whatever virus might trigger the next respiratory pandemic.
Mimicking lung epithelial cells and immune cells
Since the novel coronavirus often infects lung epithelial cells as the first step in COVID-19 infection, Zhang and his colleagues reasoned that it would make sense to cloak a nanoparticle in fragments of the outer membranes of lung epithelial cells to see if the virus could be tricked into latching on it instead of a lung cell.
Macrophages, which are white blood cells that play a major role in inflammation, also are very active in the lung during the course of a COVID-19 illness, so Zhang and colleagues created a second sponge cloaked in macrophage membrane.
The research team plans to study whether the macrophage sponges also have the ability to quiet cytokine storms in COVID-19 patients.
“We will see if the macrophage nanosponges can neutralize the excessive amount of these cytokines as well as neutralize the virus,” said Zhang.
Using macrophage cell fragments as cloaks builds on years of work to develop therapies for sepsis using macrophage nanosponges.
In a paper published in 2017 in Proceedings of the National Academy of Sciences, Zhang and a team of researchers at UC San Diego showed that macrophage nanosponges can safely neutralize both endotoxins and pro-inflammatory cytokines in the bloodstream of mice. A San Diego biotechnology company co-founded by Zhang called Cellics Therapeutics is working to translate this macrophage nanosponge work into the clinic.
A potential COVID-19 therapeutic The COVID-19 nanosponge platform has significant testing ahead of it before scientists know whether it would be a safe and effective therapy against the virus in humans, Zhang cautioned [emphasis mine]. But if the sponges reach the clinical trial stage, there are multiple potential ways of delivering the therapy that include direct delivery into the lung for intubated patients, via an inhaler like for asthmatic patients, or intravenously, especially to treat the complication of cytokine storm.
A therapeutic dose of nanosponges might flood the lung with a trillion or more tiny nanosponges that could draw the virus away from healthy cells. Once the virus binds with a sponge, “it loses its viability and is not infective anymore, and will be taken up by our own immune cells and digested,” said Zhang.
“I see potential for a preventive treatment, for a therapeutic that could be given early because once the nanosponges get in the lung, they can stay in the lung for some time,” Zhang said. “If a virus comes, it could be blocked if there are nanosponges waiting for it.”
Growing momentum for nanosponges
Zhang’s lab at UC San Diego created the first membrane-cloaked nanoparticles over a decade ago. The first of these nanosponges were cloaked with fragments of red blood cell membranes. These nanosponges are being developed to treat bacterial pneumonia and have undergone all stages of pre-clinical testing by Cellics Therapeutics, the San Diego startup cofounded by Zhang. The company is currently in the process of submitting the investigational new drug (IND) application to the FDA for their lead candidate: red blood cell nanosponges for the treatment of methicillin-resistant staphylococcus aureus (MRSA) pneumonia. The company estimates the first patients in a clinical trial will be dosed next year.
The UC San Diego researchers have also shown that nanosponges can deliver drugs to a wound site; sop up bacterial toxins that trigger sepsis; and intercept HIV before it can infect human T cells.
The basic construction for each of these nanosponges is the same: a biodegradable, FDA-approved polymer core is coated in a specific type of cell membrane, so that it might be disguised as a red blood cell, or an immune T cell or a platelet cell. The cloaking keeps the immune system from spotting and attacking the particles as dangerous invaders.
“I think of the cell membrane fragments as the active ingredients. This is a different way of looking at drug development,” said Zhang. “For COVID-19, I hope other teams come up with safe and effective therapies and vaccines as soon as possible. At the same time, we are working and planning as if the world is counting on us.”
I wish the researchers good luck. For the curious, here’s a link to and a citation for the paper,
Assuming you’d be happy with limiting the damage for rheumatoid arthritis, at some point in the future, this research looks promisin. Right now it appears the researchers aren’t anywhere close to a clinical trial. From a Sept. 3, 2018 news item on ScienceDaily,
Engineers at the University of California San Diego [UCSD] have developed neutrophil “nanosponges” that can safely absorb and neutralize a variety of proteins that play a role in the progression of rheumatoid arthritis. Injections of these nanosponges effectively treated severe rheumatoid arthritis in two mouse models. Administering the nanosponges early on also prevented the disease from developing.
“Nanosponges are a new paradigm of treatment to block pathological molecules from triggering disease in the body,” said senior author Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering. “Rather than creating treatments to block a few specific types of pathological molecules, we are developing a platform that can block a broad spectrum of them, and this way we can treat and prevent disease more effectively and efficiently.”
This work is one of the latest examples of therapeutic nanosponges developed by Zhang’s lab. Zhang, who is affiliated with the Institute of Engineering in Medicine and Moores Cancer Center at UC San Diego, and his team previously developed red blood cell nanosponges to combat and prevent MRSA infections and macrophage nanosponges to treat and manage sepsis.
Illustration of a neutrophil cell membrane-coated nanoparticle.
The new nanosponges are nanoparticles of biodegradable polymer coated with the cell membranes of neutrophils, a type of white blood cell.
Neutrophils are among the immune system’s first responders against invading pathogens. They are also known to play a role in the development of rheumatoid arthritis, a chronic autoimmune disease that causes painful inflammation in the joints and can ultimately lead to damage of cartilage and bone tissue.
When rheumatoid arthritis develops, cells in the joints produce inflammatory proteins called cytokines. Release of cytokines signals neutrophils to enter the joints. Once there, cytokines bind to receptors on the neutrophil surfaces, activating them to release more cytokines, which in turn draws more neutrophils to the joints and so on.
The nanosponges essentially nip this inflammatory cascade in the bud. By acting as tiny neutrophil decoys, they intercept cytokines and stop them from signaling even more neutrophils to the joints, reducing inflammation and joint damage.
These nanosponges offer a promising alternative to current treatments for rheumatoid arthritis. Some monoclonal antibody drugs, for example, have helped patients manage symptoms of the disease, but they work by neutralizing only specific types of cytokines. This is not sufficient to treat the disease, said Zhang, because there are so many different types of cytokines and pathological molecules involved.
“Neutralizing just one or two types might not be as effective. So our approach is to take neutrophil cell membranes, which naturally have receptors to bind all these different types of cytokines, and use them to manage an entire population of inflammatory molecules,” said Zhang.
“This strategy removes the need to identify specific cytokines or inflammatory signals in the process. Using entire neutrophil cell membranes, we’re cutting off all these inflammatory signals at once,” said first author Qiangzhe Zhang, a Ph.D. student in Professor Liangfang Zhang’s research group at UC San Diego.
To make the neutrophil nanosponges, the researchers first developed a method to separate neutrophils from whole blood. They then processed the cells in a solution that causes them to swell and burst, leaving the membranes behind. The membranes were then broken up into much smaller pieces. Mixing them with ball-shaped nanoparticles made of biodegradable polymer fused the neutrophil cell membranes onto the nanoparticle surfaces.
“One of the major challenges of this work was streamlining this entire process, from isolating neutrophils from blood to removing the membranes, and making this process repeatable. We spent a lot of time figuring this out and eventually created a consistent neutrophil nanosponge production line,” said Qiangzhe Zhang.
In mouse models of severe rheumatoid arthritis, injecting nanosponges in inflamed joints led to reduced swelling and protected cartilage from further damage. The nanosponges performed just as well as treatments in which mice were administered a high dose of monoclonal antibodies.
The nanosponges also worked as a preventive treatment when administered prior to inducing the disease in another group of mice.
Professor Liangfang Zhang cautions that the nanosponge treatment does not eliminate the disease. “We are basically able to manage the disease. It’s not completely gone. But swelling is greatly reduced and cartilage damage is minimized,” he said.
The team hopes to one day see their work in clinical trials.
It doesn’t sound like these nanosponges are going to help you with your hangover but should you have a snakebite, an E. coli infection or other such pore-forming toxin in your blood, engineers at the University of California at San Diego are working on a solution. From the University of California at San Diego Apr. 14, 2103 news release,
Engineers at the University of California, San Diego have invented a “nanosponge” capable of safely removing a broad class of dangerous toxins from the bloodstream – including toxins produced by MRSA, E. coli, poisonous snakes and bees. These nanosponges, which thus far have been studied in mice, can neutralize “pore-forming toxins,” which destroy cells by poking holes in their cell membranes. Unlike other anti-toxin platforms that need to be custom synthesized for individual toxin type, the nanosponges can absorb different pore-forming toxins regardless of their molecular structures. In a study against alpha-haemolysin toxin from MRSA, pre-innoculation with nanosponges enabled 89 percent of mice to survive lethal doses. Administering nanosponges after the lethal dose led to 44 percent survival.
They’ve produced a video about their work,
I like the fact that this therapy isn’t specific but can be used for different toxins (from the news release),
“This is a new way to remove toxins from the bloodstream,” said Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering and the senior author on the study. “Instead of creating specific treatments for individual toxins, we are developing a platform that can neutralize toxins caused by a wide range of pathogens, including MRSA and other antibiotic resistant bacteria,” said Zhang. The work could also lead to non-species-specific therapies for venomous snake bites and bee stings, which would make it more likely that health care providers or at-risk individuals will have life-saving treatments available when they need them most.
Here’s how the nanosponges work (from the news release),
In order to evade the immune system and remain in circulation in the bloodstream, the nanosponges are wrapped in red blood cell membranes. This red blood cell cloaking technology was developed in Liangfang Zhang’s lab at UC San Diego. The researchers previously demonstrated that nanoparticles disguised as red blood cells could be used to deliver cancer-fighting drugs directly to a tumor. …
Red blood cells are one of the primary targets of pore-forming toxins. When a group of toxins all puncture the same cell, forming a pore, uncontrolled ions rush in and the cell dies.
The nanosponges look like red blood cells, and therefore serve as red blood cell decoys that collect the toxins. The nanosponges absorb damaging toxins and divert them away from their cellular targets. The nanosponges had a half-life of 40 hours in the researchers’ experiments in mice. Eventually the liver safely metabolized both the nanosponges and the sequestered toxins, with the liver incurring no discernible damage. [emphasis mine]
It’s reassuring to see that this therapy doesn’t damage as it heals.
For those interested, here’s some technical information about how the nanosponges are created in the laboratory (from the news release),
Each nanosponge has a diameter of approximately 85 nanometers and is made of a biocompatible polymer core wrapped in segments of red blood cells membranes.
Zhang’s team separates the red blood cells from a small sample of blood using a centrifuge and then puts the cells into a solution that causes them to swell and burst, releasing hemoglobin and leaving RBC [red blood cell] skins behind. The skins are then mixed with the ball-shaped nanoparticles until they are coated with a red blood cell membrane.
Just one red blood cell membrane can make thousands of nanosponges, which are 3,000 times smaller than a red blood cell. With a single dose, this army of nanosponges floods the bloodstream, outnumbering red blood cells and intercepting toxins. Based on test-tube experiments, the number of toxins each nanosponge could absorb depended on the toxin. For example, approximately 85 alpha-haemolysin toxin produced by MRSA, 30 stretpolysin-O toxins and 850 melittin monomoers, which are part of bee venom.
In mice, administering nanosponges and alpha-haemolysin toxin simultaneously at a toxin-to-nanosponge ratio of 70:1 neutralized the toxins and caused no discernible damage.
This seems like promising work and, hopefully, they will be testing these nanosponges in human clinical trials soon.
Here’s a link to and a citation for the researchers’ paper,
The nanosponges that have been developed by a joint team of Rice University and Penn State University researchers look pretty exciting (wish I could write a better headline about them). Here’s the researcher describing them,
I find the idea that the sponges can be reused and the oil still put to use quite compelling. From the April 16, 2012 news item on Nanowerk,
… Daniel Hashim, a graduate student in the Rice lab of materials scientist Pulickel Ajayan, said the blocks are both superhydrophobic (they hate water, so they float really well) and oleophilic (they love oil). The nanosponges, which are more than 99 percent air, also conduct electricity and can easily be manipulated with magnets.
To demonstrate, Hashim dropped the sponge into a dish of water with used motor oil floating on top. The sponge soaked it up. He then put a match to the material, burned off the oil and returned the sponge to the water to absorb more. The robust sponge can be used repeatedly and stands up to abuse; he said a sample remained elastic after about 10,000 compressions in the lab. The sponge can also store the oil for later retrieval, he said.
“These samples can be made pretty large and can be easily scaled up,” said Hashim, holding a half-inch square block of billions of nanotubes. “They’re super-low density, so the available volume is large. That’s why the uptake of oil can be so high.” He said the sponges described in the paper can absorb more than a hundred times their weight in oil.
Nanosponges have been made from carbon nan0tubes before now (from the Feb. 8, 2010 article by Michael Berger on Nanowerk),
Carbon nanotubes (CNTs) are ‘strange’ nanostructures in a sense that they have both high mechanical strength and extreme flexibility. Deforming a carbon nanotube into any shape would not easily break the structure, and it recovers to original morphology in perfect manner. Researchers in China are exploiting this phenomenon by making CNT sponges consisting of a large amount of interconnected nanotubes, thus showing a combination of useful properties such as high porosity, super elasticity, robustness, and little weight (1% of water density).
The nanotube sponges not only show exciting properties as a porous material but they also are very promising to be used practically in a short time. The production method is simple and scalable, the cost is low, and the sponges can find immediate use in many fields related to water purification.
“We hope to give an example to industry that this sponge is a real thing they can prepare at low cost, make versatile products with high performance, and solve environmental problems utilizing nanotechnology,” [says] Anyuan Cao, a professor in the Department of Advanced Materials and Nanotechnology at Peking University …
The difference between the nanosponges made in 2010 and the ones made in 2012 is the fabrication process. From the April 16, 2012 news item on Nanowerk,
Ajayan, Rice’s Benjamin M. and Mary Greenwood Anderson Professor in Mechanical Engineering and Materials Science and of chemistry, said multiwalled carbon nanotubes grown on a substrate via chemical vapor deposition usually stand up straight without any real connections to their neighbors. But the boron-introduced defects induced the nanotubes to bond at the atomic level, which tangled them into a complex network. Nanotube sponges with oil-absorbing potential have been made before (see paper in Advanced Materials: “Carbon Nanotube Sponges”), but this is the first time the covalent junctions between nanotubes in such solids have been convincingly demonstrated, he said.
“The interactions happen as they grow, and the material comes out of the furnace as a solid,” Ajayan said. [emphasis mine] “People have made nanotube solids via post-growth processing but without proper covalent connections. The advantage here is that the material is directly created during growth and comes out as a cross-linked porous network.
By comparison, the team in China used this process (from the Feb. 8, 2012 article),
The scientists synthesized the sponges by a chemical vapor deposition (CVD) process during which the CNTs (multi-walled nanotubes with diameters in the range of 30 to 50nm and lengths of tens to hundreds of micrometers,) self-assembled into a porous, interconnected, three-dimensional framework.
The research team had collaborators from the US, Mexico, Japan, Spain, and Belgium. From the April 16, 2012 news release on EurekAlert,
When he was an undergraduate student of Ajayan’s at Rensselaer Polytechnic Institute, Hashim and his classmates discovered hints of a topological solution to the problem while participating in a National Science Foundation exchange program at the Institute of Scientific Research and Technology (IPICYT) in San Luis Potosí, Mexico. The paper’s co-author, Mauricio Terrones, a professor of physics, materials science and engineering at Penn State University with an appointment at Shinshu University, Japan, led a nanotechnology lab there.
“Our goal was to find a way to make three-dimensional networks of these carbon nanotubes that would form a macroscale fabric — a spongy block of nanotubes that would be big and thick enough to be used to clean up oil spills and to perform other tasks,” Terrones said. “We realized that the trick was adding boron — a chemical element next to carbon on the periodic table — because boron helps to trigger the interconnections of the material. To add the boron, we used very high temperatures and we then ‘knitted’ the substance into the nanotube fabric.”
For anyone who would like to read further about this work (from the April 16, 2012 news release on EurekAlert),
The paper’s co-authors are Narayanan Narayanan, Myung Gwan Hahm, Joseph Suttle and Robert Vajtai, all of Rice; Jose Romo-Herrera of the University of Vigo, Spain; David Cullen and Bobby Sumpter of Oak Ridge National Laboratory, Oak Ridge, Tenn.; Peter Lezzi and Vincent Meunier of Rensselaer Polytechnic Institute; Doug Kelkhoff of the University of Illinois at Urbana-Champaign; E. Muñoz-Sandoval of the Instituto de Microelectrónica de Madrid; Sabyasachi Ganguli and Ajit Roy of the Air Force Research Laboratory, Dayton, Ohio (on loan from IPICYT); David Smith of Arizona State University; and Humberto Terrones of Oak Ridge National Lab and the Université Catholique de Louvain, Belgium.