A delivery system that uses lipid nanoparticles to sneak proteins into cells can accomplish the same feat with smuggling therapeutic antibodies, new research has found.
The platform, reported June 23 in the Proceedings of the National Academy of Sciences, was demonstrated to inhibit cancer cells, lung inflammation and Parkinson’s disease. The lead author is Azmain Alamgir, Ph.D. ’24, currently a postdoctoral researcher at the Massachusetts Institute of Technology.
The initial technology grew out of a collaboration between the paper’s co-senior authors, Chris Alabi, the Fred H. Rhodes Professor of Chemical Engineering and Matt DeLisa, the William L. Lewis Professor of Engineering and director of the Cornell Institute of Biotechnology, both in the Cornell Duffield College of Engineering.
Alabi and DeLisa originally sought to combine their expertise in intracellular delivery of biologics and designing protein-based therapeutics, respectively. In 2024, they unveiled a generalizable technique to “cloak” proteins by remodeling their surfaces with a negatively charged ion, which enabled the proteins to electrostatically join with positively charged lipid nanoparticles – basically tiny bubbles of fat. The nanoparticles then smuggled their cumbersome cargo into living cells. Once inside, the proteins uncloak and exert their therapeutic effect, where it can have the greatest impact.
After that paper was published, researchers from the Schroeder lab at the Technion-Israel Institute of Technology, who had previously attempted antibody delivery using liposomal formulations, recognized the cloaking approach as a potential solution for delivering anti-alpha-synuclein antibodies into brain cells to target the driver of Parkinson’s disease.
“Therapeutic antibodies have transformed medicine, with several FDA-approved antibody drugs now targeting diseases from cancer to autoimmune conditions,” Alabi said. “But nearly every one of them works on targets that sit outside the cell, primarily because a 150-kilodalton antibody simply cannot cross the cell membrane on its own. Our technology changes that equation. For the first time, we can take clinically validated antibodies and deliver them to targets that are in the cell, where many of the most compelling disease drives actually reside.”
The Cornell team supplied their cloaking technology – a sulfonate group known as SL4 – as well as the protocol for deploying it, and Avi Schroeder’s team successfully applied it to the alpha-synuclein-specific antibodies that can inhibit Parkinson’s disease.
“This was one of the first instances where we essentially just shipped the material out and gave them the protocol,” Alabi said. “It was satisfying to see that someone else in a completely different country under completely different conditions could take our material, apply it the way we had reported and get a positive outcome. And this was a huge leap for us because this technology is not limited to a cell culture dish. We now have evidence that it works in a living system, reproduced independently by researchers on a different continent. That is a meaningful benchmark for any platform technology seeking clinical translation.”
Alabi’s team concurrently designed their own clinical demonstration with commercial anti-NF-kB antibodies and applied them to a very different target, one that drives extensive lung inflammation in a mouse model of acute lung injury.
“What distinguishes this paper from our earlier work is the breadth of translational evidence we were able to generate,” Alabi said. “We showed we could take a look at two different clinical indications, one in the brain, one in lungs, and we could apply this cloaked antibody system delivered with a lipid nanoparticle to vastly different targets and show improved delivery in the brain and therapeutic benefit in the lungs.”
The researchers are now interested in exploring groups other than sulfonates that might also have cloaking capabilities. Alabi, DeLisa and Alamgir have also launched their own company, Cloak Bio, to pursue additional direct therapeutic avenues.
“We are excited to get this material into the hands of other people and see what they do with it,” Alabi said.
Co-authors include postdoctoral researcher Militsa Yaneva and doctoral student Souvik Ghosal; and Schroeder, Patricia Mora-Raimundo, Anas Odeh and Peleg Hasson of the Technion-Israel Institute of Technology.
The research was supported by the Ignite Fellow for New Ventures program and the National Institutes of Health’s National Institute of General Medical Sciences.
