Engineers at the University of California, San Diego (UCSD) have developed modular nanoparticles that can be easily customized to target different biological entities such as tumors, viruses, or toxins. The surface of the nanoparticles is engineered to host any biological molecules of choice, making it possible to tailor the nanoparticles for a wide array of applications, ranging from targeted drug delivery to neutralizing biological agents.
The findings are published in Nature Nanotechnology in an article titled,
A modular approach to enhancing cell membrane-coated nanoparticle functionality using genetic engineering.”
“Since their initial development, cell membrane-coated nanoparticles (CNPs) have become increasingly popular in the biomedical field,” wrote the researchers. “Despite their inherent versatility and ability to enable complex biological applications, there is considerable interest in augmenting the performance of CNPs through the introduction of additional functionalities. Here we demonstrate a genetic-engineering-based modular approach to CNP functionalization that can encompass a wide range of ligands onto the nanoparticle surface.”
“This is a plug-and-play platform technology that allows for rapid modification of a functional biological nanoparticle,” said Liangfang Zhang, PhD, a professor of nanoengineering at the UCSD Jacobs School of Engineering.
The modular nanoparticles consist of biodegradable polymer cores coated with genetically modified cell membranes. The key to their modular design is a pair of synthetic proteins, known as SpyCatcher and SpyTag, that are specifically designed to spontaneously—and exclusively—bind with each other.
SpyCatcher is embedded onto the nanoparticle surface, while SpyTag is chemically linked to a protein of interest, such as one targeting tumors or viruses. When SpyTag-linked proteins come into contact with SpyCatcher-decorated nanoparticles, they bind to each other, enabling proteins of interest to be effortlessly attached to the nanoparticle surface.
“It’s a very simple, streamlined, and straightforward approach to functionalizing nanoparticles for any biological application,” said Zhang.
To create the modular nanoparticles, the researchers first genetically engineered human embryonic kidney (HEK) 293 cells—a commonly used cell line in biological research—to express SpyCatcher proteins on their surface. The cell membranes were then isolated, broken into smaller pieces, and coated onto biodegradable polymer nanoparticles.
These nanoparticles were subsequently mixed with SpyTag-linked proteins. In this study, the researchers used two different proteins: one targeting the epidermal growth factor receptor (EGFR) and the other targeting human epidermal growth factor receptor 2 (HER2), both of which are prevalent on the surface of various cancer cells.
As a proof of concept, the researchers tested these nanoparticles in mice with ovarian tumors. The nanoparticles were loaded with docetaxel, a chemotherapy medication, and administered to mice via intravenous injection every three days for a total of four injections. Treatment with these nanoparticles suppressed tumor growth while improving survival rate. Treated mice had a median survival of 63 to 71 days, while the median survival of untreated mice was 24 to 29 days.
The researchers are looking to further improve the modular nanoparticle platform for targeted drug delivery.
“Because we have a modular nanoparticle base, we can easily attach a neutralizing agent on the surface to neutralize viruses and biological toxins,” Zhang added. “There is also potential for creating vaccines by attaching an antigen on the nanoparticle surface using this modular platform. This opens the door to a variety of new therapeutic approaches.”