By adjusting the chemical structure of lipid nanoparticles (LNPs), Penn Engineers have discovered how to target specific organs, a major breakthrough in precision medicine. (Love Employee via Getty Images)
Penn Engineers have discovered a novel means of directing lipid nanoparticles (LNPs), the revolutionary molecules that delivered the COVID-19 vaccines, to target specific tissues, presaging a new era in personalized medicine and gene therapy.
While past research — including at Penn Engineering — has screened “libraries” of LNPs to find specific variants that target organs like the lungs, this approach is akin to trial and error. “We’ve never understood how the structure of one key component of the LNP, the ionizable lipid, determines the ultimate destination of LNPs to organs beyond the liver,” says Michael J. Mitchell, Associate Professor in Bioengineering.
In a new paper published in Nature Nanotechnology, Mitchell’s group describes how subtle adjustments to the chemical structure of the ionizable lipid, a key component of the LNP, allows for tissue-specific delivery, in particular to the liver, lungs and spleen.
Left to right: Hong-Huy Tran, Chrissie Jaruchotiratanasakul, Manali Mahajan (Photo Courtesy of CiPD)
The Center for Innovation and Precision Dentistry (CiPD), a collaboration between Penn Engineering and Penn Dental Medicine, has partnered with Wharton’s Mack Institute for Innovation Management on a research project which brings robotics to healthcare. More specifically, this project will explore potential uses of nanorobot technology for oral health care. The interdisciplinary partnership brings together three students from different Penn programs to study the commercialization of a new technology that detects and removes harmful dental plaque.
“Our main goal is to bring together dental medicine and engineering for out-of-the-box solutions to address unresolved problems we face in oral health care,” says Hyun (Michel) Koo, Co-Founding Director of CiPD and Professor of Orthodontics. “We are focused on affordable solutions and truly disruptive technologies, which at the same time are feasible and translatable.”
(From left to right) Xuexiang Han, Michael Mitchell and Mohamad-Gabriel Alameh
The COVID-19 vaccine swiftly undercut the worst of the pandemic for hundreds of millions around the world. Available sooner than almost anyone expected, these vaccines were a triumph of resourcefulness and skill.
Messenger RNA vaccines, like the ones manufactured by Moderna or Pfizer/BioNTech, owed their speed and success to decades of research reinforcing the safety and effectiveness of their unique immune-instructive technology.
In addition to outlining a more flexible and effective COVID-19 vaccine, this work has potential to increase the scope of mRNA vaccines writ large, contributing to prevention and treatment for a range of different illnesses.
Michael Mitchell, associate professor in Penn Engineering’s Department of Bioengineering, Xuexiang Han, postdoctoral fellow in Mitchell’s lab, and Mohamad-Gabriel Alameh, postdoctoral fellow in Drew Weissman’s lab at Penn Medicine and incoming assistant professor in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine, recently published their findings in Nature Nanotechnology.
mRNA, or messenger ribonucleic acid, is the body’s natural go-between. mRNA contains the instructions our cells need to produce proteins that play important roles in our bodies’ health, including mounting immune responses.
The COVID-19 vaccines follow suit, sending a single strand of RNA to teach our cells how to recognize and fight the virus.
Candida albicans is a species of yeast that is a normal part of the human microbiota but can also cause severe infections that pose a significant global health risk due to their resistance to existing treatments, so much so that the World Health Organization has highlighted this as a priority issue. The picture above shows a before (left) and after (right) fluorescence image of fungal biofilms being precisely targeted by nanozyme microrobots without bonding to or disturbing the tissue sample. (Image: Min Jun Oh and Seokyoung Yoon)
Infections caused by fungi, such as Candida albicans, pose a significant global health risk due to their resistance to existing treatments, so much so that the World Health Organization has highlighted this as a priority issue.
Although nanomaterials show promise as antifungal agents, current iterations lack the potency and specificity needed for quick and targeted treatment, leading to prolonged treatment times and potential off-target effects and drug resistance.
“Candida forms tenacious biofilm infections that are particularly hard to treat,” Koo says. “Current antifungal therapies lack the potency and specificity required to quickly and effectively eliminate these pathogens, so this collaboration draws from our clinical knowledge and combines Ed’s team and their robotic expertise to offer a new approach.”
The team of researchers is a part of Penn Dental’s Center for Innovation & Precision Dentistry, an initiative that leverages engineering and computational approaches to uncover new knowledge for disease mitigation and advance oral and craniofacial health care innovation.
For this paper, published in Advanced Materials, the researchers capitalized on recent advancements in catalytic nanoparticles, known as nanozymes, and they built miniature robotic systems that could accurately target and quickly destroy fungal cells. They achieved this by using electromagnetic fields to control the shape and movements of these nanozyme microrobots with great precision.
“The methods we use to control the nanoparticles in this study are magnetic, which allows us to direct them to the exact infection location,” Steager says. “We use iron oxide nanoparticles, which have another important property, namely that they’re catalytic.”
Other authors include Min Jun Oh, Alaa Babeer, Yuan Liu, Zhi Ren, Zhenting Xiang, Yilan Miao, and Chider Chen of Penn Dental; and David P. Cormode and Seokyoung Yoon of the Perelman School of Medicine. Cormode also holds a secondary appointment in Bioengineering.
This research was supported in part by the National Institute for Dental and Craniofacial Research (R01 DE025848, R56 DE029985, R90DE031532 and; the Basic Science Research Program through the National Research Foundation of Korea of the Ministry of Education (NRF-2021R1A6A3A03044553).
University of Pennsylvania scientist Nader Engheta has been selected as a 2023 recipient of the Benjamin Franklin Medal, one of the world’s oldest science and technology awards. The laureates will be honored on April 27 at a ceremony at the Franklin Institute in Philadelphia.
Engheta, H. Nedwill Ramsey Professor in Electrical and Systems Engineering, is among nine outstanding individuals recognized with Benjamin Franklin Medals this year for their achievements in extraordinary scientific, engineering and business leadership.
“As a scientist and a Philadelphian, I am deeply honored and humbled to receive the Franklin Medal. It is the highest compliment to receive an award whose past recipients include some of my scientific heroes such as Albert Einstein, Nikola Tesla, Alexander Graham Bell, and Max Planck. I am very thankful to the Franklin Institute for bestowing this honor upon me.”
Larry Dubinski, President and CEO of The Franklin Institute, says, “We are proud to continue The Franklin Institute’s longtime legacy of recognizing individuals for their contributions to humanity. These extraordinary advancements in areas of such importance as social equity, sustainability, and safety are significantly moving the needle in the direction of positive change and therefore laying the groundwork for a remarkable future.”
The 2023 Benjamin Franklin Medal in Electrical Engineering goes to Engheta for his transformative innovations in engineering novel materials that interact with electromagnetic waves in unprecedented ways, with broad applications in ultrafast computing and communication technologies.
“Professor Engheta’s pioneering work in metamaterials and nano-optics points the way to new and truly revolutionary computing capabilities in the future,” says University of Pennsylvania President Liz Magill. “Penn inaugurated the age of computers by creating the world’s first programmable digital computer in 1945. Professor Engheta’s work continues this tradition of groundbreaking research and discovery that will transform tomorrow. We are thrilled to see him receive the recognition of the Benjamin Franklin Medal.”
Engheta founded the field of optical nanocircuits (“optical metatronics”), which merges nanoelectronics and nanophotonics. He is also known for establishing and& developing the field of near-zero-index optics and epsilon-near-zero (ENZ) materials with near-zero electric permittivity. Through his work he has opened many new frontiers, including optical computation at the nanoscale and scattering control for cloaking and transparency. His work has far-reaching implications in various branches of electrical engineering, materials science, optics, microwaves, and quantum electrodynamics.
“This award recognizes Dr. Engheta’s trailblazing advances in engineering and physics,” says Vijay Kumar, Nemirovsky Family Dean of Penn Engineering.“ The swift and sustainable technologies his research in metamaterials and metatronics offers the world are the result of a lifelong commitment to scientific curiosity. For over 35 years, Nader Engheta has personified Penn Engineering’s mission of inventing the future.”
Nader Engheta is the H. Nedwill Ramsey Professor in the Departments of Electrical and Systems Engineering and Bioengineering in the School of Engineering and Applied Science and professor of physics and astronomy in the School of Arts & Sciences at the University of Pennsylvania.
In a proof-of-concept study, researchers from the School of Dental Medicine and School of Engineering and Applied Science shows that a hands-free system could effectively automate the treatment and removal of tooth-decay-causing bacteria and dental plaque. (Illustration: Melissa Pappas)
A shapeshifting robotic microswarm may one day act as a toothbrush, rinse, and dental floss in one.
The technology, developed by a multidisciplinary team at the University of Pennsylvania, is poised to offer a new and automated way to perform the mundane but critical daily tasks of brushing and flossing. It’s a system that could be particularly valuable for those who lack the manual dexterity to clean their teeth effectively themselves.
The building blocks of these microrobots are iron oxide nanoparticles that have both catalytic and magnetic activity. Using a magnetic field, researchers could direct their motion and configuration to form either bristlelike structures that sweep away dental plaque from the broad surfaces of teeth, or elongated strings that can slip between teeth like a length of floss. In both instances, a catalytic reaction drives the nanoparticles to produce antimicrobials that kill harmful oral bacteria on site.
Experiments using this system on mock and real human teeth showed that the robotic assemblies can conform to a variety of shapes to nearly eliminate the sticky biofilms that lead to cavities and gum disease. The Penn team shared their findings establishing a proof-of-concept for the robotic system in the journal ACS Nano.
“Routine oral care is cumbersome and can pose challenges for many people, especially those who have hard time cleaning their teeth” says Hyun (Michel) Koo, a professor in the Department of Orthodontics and divisions of Community Oral Health and Pediatric Dentistry in Penn’s School of Dental Medicine and co-corresponding author on the study. “You have to brush your teeth, then floss your teeth, then rinse your mouth; it’s a manual, multistep process. The big innovation here is that the robotics system can do all three in a single, hands-free, automated way.”
Hyun (Michel) Koo is a professor in the Department of Orthodontics and divisions of Community Oral Health and Pediatric Dentistry in the School of Dental Medicine, co-director of the Center for Innovation & Precision Dentistry, and member of the Penn Bioengineering Graduate Group at the University of Pennsylvania.
Edward Steager is a senior research investigator in Penn’s School of Engineering and Applied Science.
Koo and Steager’s coauthors on the paper are Penn Dental Medicine’s Min Jun Oh, Alaa Babeer, Yuan Liu, and Zhi Ren and Penn Engineering’s Jingyu Wu, David A. Issadore, Kathleen J. Stebe, and Daeyeon Lee.
This work was supported in part by the National Institute for Dental and Craniofacial Research (grants DE025848 and DE029985), Procter & Gamble, and the Postdoctoral Research Program of Sungkyunkwan University.
César de la Fuente, Presidential Assistant Professor in Bioengineering, Microbiology, Psychiatry, and Chemical and Biomolecular Engineering, co-led a team of researchers who created autonomous particles covered with patches of protein “motors,” with the goal that these bots can eventually carry livesaving drugs through bodily fluids.
This scProteome-seq array shows separated protein biomarkers (green and magenta spots) from thousands of single cells.
Penn Health-Tech’s Nemirovsky Engineering and Medicine Opportunity (NEMO) Prize awards $80,000 to support early-stage ideas joining engineering and medicine. The goal of the prize is to encourage collaboration between the University of Pennsylvania’s Perelman School of Medicine and the School of Engineering and Applied Science by supporting innovative ideas that might not receive funding from traditional sources.
This year, the NEMO Prize has been awarded to a team of researchers from Penn Engineering’s Department of Bioengineering. Their project aims to develop a technology that can detect multiple cancer biomarkers in single cells from tumor biopsy samples.
As cancer cells grow in the body, one of the characteristics that influences tumor growth and response to treatment is cancer cell state heterogeneity, or differences in cell states. Methods that rapidly catalogue cell heterogeneity may be able to detect rare cells responsible for tumor growth and drug resistance.
Single-cell transcriptomics (scRNA-seq) is the standard method for studying cell states; by amplifying and analyzing the cell’s complement of RNA sequences at a given time, researchers can get a snapshot of what proteins the cell is in the process of making. However, this method does not fully capture the function of the cell. The field of proteomics, which captures the actual protein content of cells along with post-translational modifications, provides a better picture of the cell’s function, but single-cell proteomic methods with the same sensitivity as scRNA-seq do not currently exist.
Alex Hughes, Lukasz Bugaj and Andrew Tsourkas
This collaborative project, which joins Assistant Professors Alex Hughes and Lukasz Bugaj, as well as Professor Andrew Tsourkas, aims to change that by developing multiplexed, sensitive and highly specific single-cell proteomics technologies to advance our understanding of cancer, its detection and its treatment.
This new technology, called scProteome-seq, builds from Hughes’s previous work.
“My specific expertise here is as an inventor of single-cell western blotting, which is the core technology that our team is building on,” says Hughes. “Single-cell proteomics technologies of this type have a track-record of commercial translation for applications in basic science and clinical automation, so our approach has a high potential for real-world impact.”
The current technology from Hughes’ lab separates proteins in cells by their molecular weight and “blots” them on a piece of paper. Improvements to this technology included in this project will remove the limitation of using light-emitting dyes to detect different proteins and instead use DNA barcodes to differentiate them.
As part of a major University-wide investment in science, engineering, and medicine, the Innovation in Data Engineering and Science Initiative aims to help Penn become a leader in developing data-driven approaches that can transform scientific discovery, engineering research, and technological innovation.
From smartphones and fitness trackers to social media posts and COVID-19 cases, the past few years have seen an explosion in the amount and types of data that are generated daily. To help make sense of these large, complex datasets, the field of data science has grown, providing methodologies, tools, and perspectives across a wide range of academic disciplines.
As part of its $750 million investment in science, engineering, and medicine, the University has committed to supporting the future needs of this field. To this end, the Innovation in Data Engineering and Science (IDEAS) initiative will help Penn become a leader in developing data-driven approaches that can transform scientific discovery, engineering research, and technological innovation.
“The IDEAS initiative is game-changing for our University,” says President Amy Gutmann. “This new investment allows us to boost our interdisciplinary efforts across campus, recruit phenomenal additional team members, and generate an even more sound foundation for discovery, experimentation, and design. This initiative is a clear statement that Penn is committed to taking data science head-on.”
“One of the unique things about data science and data engineering is that it’s a very horizontal technology, one that is going to be impacting every department on campus,” says George Pappas, Electrical and Systems Engineering Department chair. “When you have a horizontal technology in a competitive area, we have to figure out specific areas where Penn can become a worldwide leader.”
To do this, IDEAS aims to recruit new faculty across three research areas: artificial intelligence (AI) to transform scientific discovery, trustworthy AI for autonomous systems, and understanding connections between the human brain and AI.
In the area of neuroscience and how the human brain is similar to AI and machine learning approaches, research from PIK Professor Konrad Kording and Dani Bassett’sComplex Systems lab exemplifies the types of cross-disciplinary efforts that are essential for addressing complex questions. By recruiting additional faculty in this area, IDEAS will help Penn make strides in bio-inspired computing and in future life-changing discoveries that could address cognitive disorders and nervous system diseases.
Michael Mitchell, Sarah Shepherd and David Issadore pose with their new device.
The COVID vaccines currently being deployed were developed with unprecedented speed, but the mRNA technology at work in some of them is an equally impressive success story. Because any desired mRNA sequence can be synthesized in massive quantities, one of the biggest hurdles in a variety of mRNA therapies is the ability to package those sequences into the lipid nanoparticles that deliver them into cells.
Now, thanks to manufacturing technology developed by bioengineers and medical researchers at the University of Pennsylvania, a hundred-fold increase in current microfluidic production rates may soon be possible.
The researchers’ advance stems from their design of a proof-of-concept microfluidic device containing 128 mixing channels working in parallel. The channels mix a precise amount of lipid and mRNA, essentially crafting individual lipid nanoparticles on a miniaturized assembly line.
This increased speed may not be the only benefit; more precisely controlling the nanoparticles’ size could make treatments more effective. The researchers tested the lipid nanoparticles produced by their device in a mouse study, showing they could deliver therapeutic RNA sequences with four-to-five times greater activity than those made by conventional methods.
The study was led by Michael Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, and David Issadore, Associate Professor in Penn Engineering’s Department of Bioengineering, along with Sarah Shepherd, a doctoral student in both of their labs. Rakan El-Mayta, a research engineer in Mitchell’s lab, and Sagar Yadavali, a postdoctoral researcher in Issadore’s lab, also contributed to the study.
They collaborated with several researchers at Penn’s Perelman School of Medicine: postdoctoral researcher Mohamad-Gabriel Alameh, Lili Wang, Research Associate Professor of Medicine, James M. Wilson, Rose H. Weiss Orphan Disease Center Director’s Professor in the Department of Medicine, Claude Warzecha, a senior research investigator in Wilson’s lab, and Drew Weissman, Professor of Medicine and one of the original developers of the technology behind mRNA vaccines.
“We believe that this microfluidic technology has the potential to not only play a key role in the formulation of current COVID vaccines,” says Mitchell, “but also to potentially address the immense need ahead of us as mRNA technology expands into additional classes of therapeutics.”
