Nanotechnology

Advances in drug delivery: A new framework linking lipid nanoparticle structure and immune responses

Diagram of receptors protruding from the cell membrane. The red molecule approaches the receptor cavity. The membrane consists of two layers of molecules, with a purple head on the outside and an orange tail on the inside. Credit: Carnegie Mellon University Chemical Engineering

A new framework fills a gap in our understanding of RNA therapeutics by linking the structure of lipid nanoparticles to immune responses. This will help scientists and engineers expand the use of RNA medicines beyond vaccines to other therapeutic applications.

Decades of research have led to lipid nanoparticle structures that deliver RNA to specific locations within the body. This basic research is one reason why mRNA COVID-19 vaccines were able to be developed so quickly during the pandemic.

However, with the primary focus on the delivery mechanism, less attention has been paid to the immune response to the delivery vehicle. Scientists do not know how different lipid nanoparticle structures interact with the immune system. Kathryn Whitehead and her lab at Carnegie Mellon University are working to fill in the missing information.

Expanding the use of lipid nanoparticles beyond RNA vaccines requires establishing the relationship between lipid chemistry and immune responses.

Cells in the body have receptors that detect pathogens and trigger an immune response. Different proteins identify different types of molecules, allowing the body to adjust its response. There are protein receptors that recognize the RNA that is characteristic of viral infections. Other protein receptors bind to lipids, which may indicate a bacterial infection.

To create nanoparticles that deliver RNA, Whitehead, a professor of chemical engineering and biomedical engineering, uses synthetic lipids. They are composed of amines containing carbon and nitrogen.

In a study recently published in Nature Biomedical Engineering, Whitehead and Namit Chaudhary link the immune response triggered by lipid nanoparticles to their lipid chemistry. Based on nitrogen chemistry, they found that some lipid structures bind very strongly to receptors, while others bind weakly. Strong interactions trigger receptors and ultimately an immune response.

Based on these findings, Whitehead and Chaudhary created a computer model that predicted which lipid nanoparticle structures would trigger an immune response. They tested their prediction experimentally.

Whitehead and Chaudhary also hypothesized that synthetic lipids interact with lipids present on cell membranes. They found that lipid nanoparticles that inhibit immune responses prevent the formation of lipid domains on the surface of cell membranes.

They interfered with signaling pathways, including those that would otherwise signal an immune response. Lipid nanoparticles that triggered an immune response interacted with cell membranes without inhibiting signaling functions.

The Whitehead Institute’s multifaceted approach uses both computational and experimental tools. They can screen thousands of molecules on a computer to identify those that show the desired response. “You can organize tens of thousands of pieces of data into manageable groups that can be synthesized in the lab and tested experimentally. You can’t do that many experiments, but you can simulate that much,” Chaudhary says. .

Chaudhary began developing the computational tool when laboratory facilities were closed due to the coronavirus pandemic. His experimental data didn’t make sense, so he turned to what he still had access to: computers. Choudhary says the lockdown forced him to ask different questions, which changed the direction of his research.

“This is a reminder that all the diverse backgrounds come together to tell a story,” he says. “The computational research is rooted in thermodynamics, which is chemical engineering, but the rest of the research is biomedical engineering and immunology.” When the lab reopened, Chaudhary said what he had seen computationally was able to be experimentally verified.

This discovery will help engineers tune immune responses when designing lipid nanoparticles for drug delivery. Using Whitehead and Chaudhary’s framework, lipids can be identified quickly and at low cost.

“In the case of vaccines, you might need something more immunogenic to make the vaccine respond better. But if you’re administering something to the brain or liver, for example, there’s a lot more potential for toxicity. “You may not want to provoke some substantial immune response,” Chaudhary explains.

He sees this framework potentially becoming part of the decision tree for developing treatments in the future.

Further information: Namit Chaudhary et al, Amine headgroups of ionizable lipids drive immune responses to lipid nanoparticles by binding to receptors TLR4 and CD1d, Nature Biomedical Engineering (2024). DOI: 10.1038/s41551-024-01256-w

Provided by Carnegie Mellon University Chemical Engineering

Citation: Advances in drug delivery: A new framework links lipid nanoparticle structures and immune responses (October 25, 2024) https://phys.org/news/2024-10-advancing-drug-delivery-framework- Retrieved October 25, 2024 from links. html

This document is subject to copyright. No part may be reproduced without written permission, except in fair dealing for personal study or research purposes. Content is provided for informational purposes only.

Related Articles

Leave a Reply

Your email address will not be published. Required fields are marked *

Back to top button