Michael Mitchell, an associate professor of bioengineering at the University, is developing novel lipid nanoparticles that can deliver mRNA inside human cells, which could pave the way for therapies that could treat cancer, lung disease, and other leading causes of death.
Mitchell leads a biomaterials and drug delivery lab at the School of Engineering and Applied Sciences, where he and his team work on engineering new biomaterials, such as LNPs, that deliver drugs and nucleic acid therapeutics to specific cells and tissues in the body.
LNPs — tiny, fatty droplets that can carry mRNA into cells — have become more prevalent after they were used as the basis of the COVID-19 vaccines to deliver mRNA to immune cells inside the arm. LNPs were the main inspiration for Mitchell’s focus on nanoparticles, he wrote in a statement to The Daily Pennsylvanian.
“We need to be able to reach different cellular targets and deliver mRNA to them to produce the therapeutic protein of interest. And the lipid nanoparticles used in the vaccines won’t work for these applications — we need new, better technology,” Mitchell wrote. “That is where my lab comes in — we design new lipid nanoparticle technology for different routes of administration to ‘hit’ different cellular targets and tissues.”
Mitchell’s lab uses a technique called microfluidics to make the LNP. A microfluidic device consists of a Y-shaped channel on a chip, where there is a lipid mixture flowing through one side of the device and RNA concentrated in an acidic citrate buffer on the other side. The mixing of these two fluids leads to a process known as chaotic mixing that causes the lipids to become charged. This charge allows the RNA to bind to the lipid.
According to Mitchell, some of the most relevant recent insights from his lab include his PhD student Ann Metzloff designing a type of LNP, known as activating LNPs, that can engineer CAR T cells.
CAR T cells are currently laborious and time consuming to manufacture. Utilizing two switches — one that activates the CAR T cells to take up the LNP, the other that allows the aLNP and mRNA to be able to be taken up — aLNP shortens the production process to under 24 hours. This research will allow CAR T therapies to become cheaper and more accessible.
Another promising result focused on designing a large library of 180 LNPs for delivering mRNA to the lungs. LNPs have primarily been designed to deliver mRNA into the liver, which limits interactions with other organs of interest. However, with these new LNPs, which were both biodegradable and stronger in potency, Mitchell and postdoctoral fellow Lulu Xue were able to achieve therapeutic mRNA delivery into the lungs, helping to eradicate metastatic lung cancer in preclinical mouse model studies.
Mitchell's lab has also designed LNPs that can theoretically deliver mRNA to the brain, one of the most difficult organs to target due to the blood-brain barrier, as well as a “space shuttle”-inspired LNP. By mimicking the design of a space shuttle, Mitchell and postdoctoral fellow Xuexiang Han generated LNPs that can more efficiently penetrate cellular targets and deliver mRNA therapeutics, such as rapidly restoring obese mouse body weight to normal levels in one example study.
“The possibilities to utilize this technology in therapeutic space are endless — by altering the mRNA sequence, we can develop therapeutics for cancer, cardiovascular disease, and neurological disorders,” Mitchell wrote.
Much of the research that Mitchell conducts correlates to advancements made by various Penn researchers.
Penn professors Drew Weissman and Katalin Karikó recently won the Nobel Prize in Physiology or Medicine for discovering how to utilize mRNA to promote the production of customized proteins from immune cells, the basis of the COVID-19 vaccines.
Penn researcher Carl June created the genetic engineering technique known as CAR T, which has been used to treat more than 20,000 patients with leukemia and other deadly blood cancers.
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